Abstract
Drug package inserts are a crucial foundation for clinical medication practices and serve as the legal basis for guiding rational drug use and ensuring patient safety and efficacy. As rare disease treatments evolve, current package inserts often need to meet the clinical requirements for treating such conditions, frequently resulting in off-label drug use. This consensus is derived from discussions between Guangdong Pharmaceutical Association Hematologic Rare Diseases Group experts. The consensus aims to provide a framework and reference for the clinical application of off-label drug use in treating rare hematologic diseases.
1 Introduction
Package inserts are crucial for the use of clinical medications and serve as the legal standard that guides clinicians and pharmacists toward rational drug use. Despite rapid advances in diagnosing and treating rare diseases, updates to package inserts lag, leading to widespread off-label drug use in clinical settings. This is often unavoidable due to the unique characteristics of the rare disease patient population. Article 29, Clause 2 of the Chinese “Law on Doctors” states “in the absence of effective or superior treatment methods and under special circumstances, physicians may use drugs not explicitly indicated in the drug instructions but supported by evidence-based medical evidence, with the patient’s informed consent.” (Physician Law on Doctors of the People’s Republic of China, 2021) However, standardized guidelines or expert consensus on off-label use for rare disease patients remain absent. Although the current progress in rare diseases has seen significant advancements, particularly in the areas of gene therapy, immunotherapy, antibody-drug conjugate agents and innovative drugs for rare hematological diseases, there are still obstacles in the accessibility of these drugs or treatments in China. The new use of old drugs still dominates the treatment of rare hematological diseases, however, off-label drug use is common because no updated of the instructions and less clinical trials for rare diseases. To address this, the Guangdong Pharmaceutical Association Rare Disease Expert Committee of the has compiled the “Expert Consensus on Off-Label Use of Drugs for Rare Hematological Diseases (2024 Edition)” (hereafter referred to as the “Consensus”). This document seeks to provide evidence-based guidance for the off-label use of commonly used drugs in the diagnosis and treatment of rare hematologic diseases, standardize related drug use, and improve pharmaceutical supervision and management in the individualized treatment of special populations. The “Consensus” is intended for use by physicians when prescribing and pharmacists when reviewing prescriptions at medical institutions. However, the management of off-label drug use in clinical practice should still adhere to the relevant regulations. Clinicians are urged to assess the benefits and risks of off-label drug use for patients and to avoid such practices whenever satisfactory clinical efficacy can be achieved with standard drug instructions.
2 Materials and methods
2.1 The consensus scope, target professionals, and target patient population
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.
2.2 The methodology of the consensus development
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 (2nd 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.
2.3 Consensus panels
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.
2.4 Evidence retrieval and data extraction
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.
2.5 Comprehensive analysis of evidence and compilation of evidence report
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.
2.6 The process of formulating recommendations
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.
3 Result
3.1 Off-label drug use for hemophilia treatment
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.
3.2 Off-label drug use for Castleman’s disease treatment
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.
TABLE 1
| Generic name | Dosage form | Off-label type | Off-label content | Specific usage | Evidence and references | Evidence level |
|---|---|---|---|---|---|---|
| Tocilizumab | Injection | Indication | Castleman’s disease (UCD and iMCD) | In countries where siltuximab is not available or approved, tocilizumab can be used | International evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease (van Rhee F, et al., 2018) International consensus diagnostic and treatment guidelines for unicentric Castleman disease (van Rhee F, et al., 2020) | Not listed in Micromedex |
| Rituximab | Injection | Indication | Castleman’s disease (UCD compression symptoms that cannot be completely resected and severe or nonsevere iMCD) | For patients unresponsive to IL-6 monoclonal antibody therapy, consider a regimen based on rituximab plus corticosteroids ± immunomodulators/immunosuppressants (second- or third-line treatments include thalidomide, cyclosporin A, sirolimus, or bortezomib) | International evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease (van Rhee F, et al., 2018) International consensus diagnostic and treatment guidelines for unicentric Castleman disease (van Rhee F, et al., 2020) | Not listed in Micromedex |
| Prednisone | Tablet | Indication | Castleman’s disease (UCD compression symptoms that cannot be completely resected and severe or non severe iMCD) | Same as rituximab | International evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease (van Rhee F, et al., 2018) International consensus diagnostic and treatment guidelines for unicentric Castleman disease (van Rhee F, et al., 2020) | Not listed in Micromedex |
| Thalidomide | Tablet | Indication | Castleman’s disease (UCD compression symptoms that cannot be completely resected and severe or non severe iMCD) | Same as rituximab | International evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease (van Rhee F, et al., 2018) International consensus diagnostic and treatment guidelines for unicentric Castleman disease (van Rhee F, et al., 2020) Chinese Consensus on Diagnosis and Treatment of Castleman’s Disease (2021) (Hematology Committee of Chinese Medical Association, et al., 2021) | Not listed in Micromedex |
| Cyclosporine | Injection/Capsule/Oral Solution | Indication | Castleman’s disease (Combination therapy for iMCD-TAFRO) | Same as rituximab | International evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease (van Rhee F, et al., 2018) International consensus diagnostic and treatment guidelines for unicentric Castleman disease (van Rhee F, et al., 2020) Chinese Consensus on Diagnosis and Treatment of Castleman’s Disease (2021) (Hematology Committee of Chinese Medical Association, et al., 2021) | Not listed in Micromedex |
| Sirolimus | Tablet/Capsule/Oral Solution | Indication | Castleman’s disease (Second line treatment of non severe iMCD) | Same as rituximab | International evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease (van Rhee F, et al., 2018) International consensus diagnostic and treatment guidelines for unicentric Castleman disease (van Rhee F, et al., 2020) Chinese Consensus on Diagnosis and Treatment of Castleman’s Disease (2021) (Hematology Committee of Chinese Medical Association, et al., 2021) | Not listed in Micromedex |
| Bortezomib | Injection | Indication | Castleman’s disease (Second line treatment of non severe iMCD) | Same as rituximab | International evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease (van Rhee F, et al., 2018) International consensus diagnostic and treatment guidelines for unicentric Castleman disease (van Rhee F, et al., 2020) Chinese Consensus on Diagnosis and Treatment of Castleman’s Disease (2021) (Hematology Committee of Chinese Medical Association, et al., 2021) | Not listed in Micromedex |
Off-label drug usage catalog for Castleman’s disease treatment.
3.3 Off-label drug use for Erdheim-Chester disease treatment
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.
TABLE 2
| Generic name | Dosage form | Off-label type | Off-label content | Specific usage | Evidence and references | Evidence level |
|---|---|---|---|---|---|---|
| Vemurafenib | Tablet | Indication | Erdheim-Chester disease | Treatment for Erdheim-Chester disease with BRAF V600 mutation, 480–960 mg orally, twice a day | FDA approved (Product Information: ZELBORAFR oral tablets, vemurafenib oral tablets, 2017) Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease (Diamond EL, et al., 2014) | Not listed in Micromedex |
| Interferon-α | Injection | Indication | Erdheim-Chester disease | 3 mIU subcutaneous injection, three times a week (standard dose); or 6–9 mIU subcutaneous injection, 3 days a week (high dose) | Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease (Diamond EL, et al., 2014) | Not listed in Micromedex |
| Pegylated Interferon-α | Injection | Indication | Erdheim-Chester disease | Subcutaneous injection of 135 μg/week (standard dose), or 180 μg/week (high dose) | Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease (Diamond EL, et al., 2014) | Not listed in Micromedex |
| Trametinib | Tablet | Indication | Erdheim-Chester disease | Used for the combined treatment of Erdheim-Chester disease with BRAF V600 and KRAS Q61H mutations | Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations (Nordmann et al., 2017) | Not listed in Micromedex |
| Cladribine | Injection | Indication | Erdheim-Chester disease | 6 mg/m2 intravenous injection, once a day for 5 consecutive days, every 4 weeks | Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease (Diamond EL, et al., 2014) | Not listed in Micromedex |
| Sirolimus | Tablet/Capsule/Oral Solution | Indication | Erdheim-Chester disease | 2 mg/day | Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial (Gianfreda et al., 2015) Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease (Diamond EL, et al., 2014) | Not listed in Micromedex |
| Prednisone | Tablet | Indication | Erdheim-Chester disease | Initial dose of 0.75 mg/kg/day, gradually reducing to 0.125–0.5 mg/kg/day over 6 months | Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial (Gianfreda et al., 2015) | Not listed in Micromedex |
Off-label drug usage catalog for erdheim-chester disease treatment.
3.4 Off-label drug use for fanconi anemia treatment
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.
TABLE 3
| Generic name | Dosage form | Off-label type | Off-label content | Specific usage | Evidence and references | Evidence level |
|---|---|---|---|---|---|---|
| Danazol | Capsule | Indication | Fanconi Anemia | Initial dosage of 200 mg per dose, 2–3 times per day. Once effective, the maintenance dosage is generally 50% or less of the initial dosage, decreased over intervals of 1–3 months or longer | Androgens and liver tumors: Fanconi’s anemia and non-Fanconi’s conditions (Velazquez and Alter, 2004) | Not listed in Micromedex |
Off-label drug usage catalog for fanconi anemia treatment.
3.5 Off-label drug use for langerhans cell histiocytosis treatment
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.
TABLE 4
| Generic name | Dosage form | Off-label type | Off-label content | Specific usage | Evidence and references | Evidence level |
|---|---|---|---|---|---|---|
| Vincristine | Injection | Indication | Langerhans Cell Histiocytosis | Initial dosage of 3.7 mg/m2 via intravenous injection. Subsequent doses are administered with increasing quantities: the second dose is 5.5 mg/m2, the third is 7.4 mg/m2, the fourth is 9.25 mg/m2, and the fifth is 11.1 mg/m2, weekly to maximum of 18.5 mg/m2 | FDA approved (Product Information: vinblastine sulfate intravenous injection, 2008) | Effectiveness Class IIa Recommendation Class IIa Evidence Level Category B |
| Cladribine | Injection | Indication | Langerhans Cell Histiocytosis (Pediatric) | In a study involving ten children with recurrent or refractory Langerhans cell histiocytosis, the initial dose of cladribine was 5 mg/m2 per day, administered for 3 days, then increased to 6.5 mg/m2 for another 3 days per cycle, for up to six cycles. The cladribine was mixed with 100 mL of saline and administered via a portable infusion pump Cladribine was effectively used to treat six children with recurrent Langerhans cell histiocytosis. The treatment involved administering cladribine intravenously at doses of 5–7 mg/m2 per day for five consecutive days, with cycles repeating every 21–28 days. The patients underwent six treatment cycles | Efficacy studies on pediatric patients with refractory Langerhans cell histiocytosis (Stine KC, et al., 2004) Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine (Rodriguez-Galindo C, et al., 2002) Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine (Dhall G, et al., 2008) | Effectiveness Class IIa Recommendation Class IIb Evidence Level Category B |
| Mechlorethamine | Tincture/Ointment | Indication | Langerhans Cell Histiocytosis | Diluted in water to 200 mg/L (0.02%). Applied topically with a swab, initial dose 2–3 mg/day, wash off after 10 min. Apply daily until lesions recede, then reduce frequency to every 2 days, then every 3 days, and weekly until clear | Long term follow up of topical Mechlorethamine treatment for cutaneous Langerhans cell histiocytosis (Hoeger PH, et al., 2000) | For adults: effectiveness Class IIa, recommendation Class IIb, evidence category C For children: effectiveness Class IIa, recommendation Class IIb, and evidence category B |
| Cyclophosphamide | Injection/Tablet | Indication | Langerhans Cell Histiocytosis | 300 mg/m2 on days 1, 8, and 15 of a 4-week cycle | Phase 2 study of oral thalidomide-cyclophosphamide-dexamethasone for recurrent/refractory adult Langerhans cell histiocytosis (Wang JN, et al., 2022) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Level Category B |
| Etanercept | Injection | Indication | Langerhans Cell Histiocytosis | 0.4 mg/kg twice weekly | Successful treatment study of Langerhans'-cell histiocytosis with etanercept (Henter JI, et al., 2001) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Level Category C |
| Cyclosporine | Injection/Capsule/Oral Solution | Indication | Langerhans Cell Histiocytosis | 12 mg/kg/day; 15–20 mg/kg/day | Multisystem Langerhans-cell histiocytosis with life-threatening pulmonary involvement--good response to cyclosporine A (Zeller B, et al., 2000) Treatment of relapsed Langerhans cell histiocytosis by cyclosporin A combined with etoposide and prednisone (Korholz D, et al., 1997) Cyclosporine therapy for advanced Langerhans cell histiocytosis (Mahmoud HH, et al., 1991) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Level Category C |
| Etoposide | Injection/Capsule | Indication | Langerhans Cell Histiocytosis | 100 mg/m2 twice weekly for 4 weeks, then once every 2–4 weeks | Etoposide in the treatment of six children with Langerhans cell histiocytosis (histiocytosis X) (Viana MB, et al., 1991) Treatment of Langerhans cell histiocytosis in children with etoposide (Ishii et al., 1992) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Level Category B |
| Pamidronate Disodium | Injection | Indication | Pain management in Langerhans Cell Histiocytosis | 90 mg IV per session, followed by monthly sessions for 4 months | Pamidronate for bone pain from osteolytic lesions in Langerhans'-cell histiocytosis (Arzoo K, et al., 2001) 2. Treatment of Langerhans cell histiocytosis with pamidronate (Farran RP, et al., 2001) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Level Category C |
Off-label drug usage catalog for langerhans cell histiocytosis treatment.
3.6 Off-label drug use for paroxysmal nocturnal hemoglobinuria treatment
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.
TABLE 5
| Generic name | Dosage form | Off-label type | Off-label content | Specific usage | Evidence and references | Evidence level |
|---|---|---|---|---|---|---|
| Deferiprone | Tablet/Oral Solution | Indication | Paroxysmal Nocturnal Hemoglobinuria | 3–6 g/day | Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multi-center trial (Kersten MJ, et al., 1996) | Not listed in Micromedex |
Off-label drug usage catalog for paroxysmal nocturnal hemoglobinuria treatment.
3.7 Off-label drug use for POEMS syndrome
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.
TABLE 6
| Generic name | Dosage form | Off-label type | Off-label content | Specific usage | Evidence and references | Evidence level |
|---|---|---|---|---|---|---|
| Lenalidomide | Capsule | Indication | POEMS Syndrome | High-dose treatment: 25 mg/day for 3 weeks, 1 week off, for 6 cycles with dexamethasone; Low-dose treatment: 10 mg/day with dexamethasone | 1. Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective open-label trial. (Nozza A, et al., 2017) 2. Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome. (Cai QQ, et al., 2015) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Category B |
| Thalidomide | Tablet | Indication | POEMS Syndrome | Combined with dexamethasone, a 28-day cycle, where dexamethasone is used at 12 mg/m2/day for the first 4 days of the cycle; Thalidomide starts at 100 mg every other day, increasing to 100 mg/day from day 8, and 200 mg/day from day 15 | 1. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. (Gavriatopoulou M, et al., 2018) 2. POEMS syndrome: 2021 Update on diagnosis risk-stratification and management.(Dispenzieri A, 2021) 3. Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre randomised double-blind placebo-controlled trial.(Diamond et al., 2014) | Not listed in Micromedex |
| Mephalan | Injection/Tablet | Indication | POEMS Syndrome | Combined with dexamethasone, dosage of 140–200 mg/m2, lower doses used for more severe cases | 1. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. (Gavriatopoulou M, et al., 2018) 2. POEMS syndrome: 2021 Update on diagnosis risk-stratification and management. (Dispenzieri A, 2021) | Not listed in Micromedex |
| Bortezomib | Injection | Indication | POEMS Syndrome | Combined with cyclophosphamide and dexamethasone: Bortezomib administered on days 1, 4, and 5 at 1 mg/m2 IV; Cyclophosphamide 200 mg on days 8 and 11; Dexamethasone 20 mg from days 1–4 and 8 to 11 | 1. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. (Gavriatopoulou M, et al., 2018) 2. POEMS syndrome: 2021 Update on diagnosis risk-stratification and management. (Dispenzieri, 2021) 3. Successful treatment of newly diagnosed POEMS syndrome with reduced-dose bortezomib based regimen.(Nordmann et al., 2017) | Not listed in Micromedex |
| Lenalidomide | Capsule | Indication | POEMS Syndrome | High-dose treatment: 25 mg/day for 3 weeks, then pause for 1 week, for 6 cycles in combination with dexamethasone; Low-dose treatment: 10 mg/day in combination with dexamethasone | 1. Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective open-label trial. (Nozza et al., 2017) 2. Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome. (Cai et al., 2015) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Category B |
| Thalidomide | Tablet | Indication | POEMS Syndrome | Combined with dexamethasone, a 28-day cycle, where dexamethasone is used at 12 mg/m2/day for the first 4 days of the cycle; Thalidomide starts at 100 mg every other day, increasing to 100 mg/day from day 8, and 200 mg/day from day 15 | 1. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. (Gavriatopoulou et al., 2018) 2. POEMS syndrome: 2021 Update on diagnosis risk-stratification and management. (Dispenzieri, 2021) 3. Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre randomised double-blind placebo-controlled trial.(Misawa et al., 2016) | Not listed in Micromedex |
| Mephalan | Injection/Tablet | Indication | POEMS Syndrome | Combined with dexamethasone, dosage of 140–200 mg/m2, lower doses used for more severe cases | 1. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. (Gavriatopoulou et al., 2018) 2. POEMS syndrome: 2021 Update on diagnosis risk-stratification and management. (Dispenzieri, 2021) | Not listed in Micromedex |
| Bortezomib | Injection | Indication | POEMS Syndrome | Combined with cyclophosphamide and dexamethasone: Bortezomib administered on days 1, 4, 8, and 11 at 1 mg/m2 IV; Cyclophosphamide 200 mg on days 8 and 11; Dexamethasone 20 mg from days 1–4 and 8 to 11 | 1. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. (Gavriatopoulou et al., 2018) 2. POEMS syndrome: 2021 Update on diagnosis risk-stratification and management. (Dispenzieri A, 2021) 3. Successful treatment of newly diagnosed POEMS syndrome with reduced-dose bortezomib based regimen.(He et al., 2018) | Not listed in Micromedex |
| Daratumumab | Injection | Indication | POEMS Syndrome | 16 mg/kg once a week | POEMS syndrome: 2021 Update on diagnosis risk-stratification and management. (Dispenzieri, 2021) | Not listed in Micromedex |
| Dexamethasone | Injection/Tablet | Indication | POEMS Syndrome | Used in combination with other chemotherapy drugs | 1. Update on the Diagnosis and Treatment of POEMS (Polyneuropathy Organomegaly Endocrinopathy Monoclonal Gammopathy and Skin Changes) Syndrome: A Review (Khouri et al., 2021) 2. POEMS syndrome: 2021 Update on diagnosis risk-stratification and management. (Dispenzieri, 2021) 3. Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre randomised double-blind placebo-controlled trial. (Misawa et al., 2016) 4. Successful treatment of newly diagnosed POEMS syndrome with reduced-dose bortezomib based regimen(He et al., 2018) | Not listed in Micromedex |
Off-label drug usage catalog for POEMS syndrome.
3.8 Off-label drug use for treating porphyria
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.
TABLE 7
| Generic name | Form | Off-label type | Off-label content | Specific usage | Evidence base and references | Evidence level |
|---|---|---|---|---|---|---|
| Hydroxychloroquine | Tablet | Indication | Alternative treatment for porphyria patients who cannot undergo or tolerate venesection | 100 mg per dose, twice a week | Consensus of Chinese Experts on Diagnosis and Treatment of Porphyria (2020), (Chinese Society of Hematology Red Blood Cell Disease Study Group, (2020) | Not listed in Micromedex |
Off-label drug usage catalog for treating porphyria.
3.9 Off-label drug use for treating primary light Chain Amyloidosis
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.
TABLE 8
| Generic name | Form | Off-label type | Off-label content | Specific usage | Evidence base and references | Evidence level |
|---|---|---|---|---|---|---|
| Bortezomib | Injection | Indication | Primary light chain amyloidosis | Used in combination with dexamethasone and/or cyclophosphamide as part of a chemotherapy regimen | 1. Management of systemic AL amyloidosis: Recommendations of the Myeloma Foundation of Australia Medical and Scientific (Weber et al., 2015) 2. Guidelines on the management of AL amyloidosis. (Wechalekar et al., 2015) 3. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: A randomized controlled trial. (Huang et al., 2014) | Effectiveness Class IIa, Recommendation Class I Evidence Category B |
| Thalidomide | Tablet | Indication | Primary light chain amyloidosis | Start with oral thalidomide 200 mg at night. If tolerated, increase dose by 200 mg/day every 2 weeks, up to a maximum of 800 mg | Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis. (Seldin et al., 2003) | Effectiveness Class IIb, Recommendation Class IIb, Evidence Category B |
| Lenalidomide | Capsule | Indication | Primary light chain amyloidosis as part of a treatment regimen | Lenalidomide 15 mg daily, orally from day 1–21 of a 28-day cycle, in combination with dexamethasone and/or cyclophosphamide | 1. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan bortezomib and thalidomide. (Palladini et al., 2012) 2. A phase II trial of cyclophosphamide lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. (Palladini et al., 2013) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Category B |
| Melphalan | Injection/Tablet | Indication | Primary light chain amyloidosis as part of a treatment regimen | 200 mg/m2 combined with autologous bone marrow transplantation | High-dose melphalan and autologous bone marrow transplantation for systemic AL amyloidosis with cardiac involvement. (Moreau et al., 1996) | Effectiveness Class IIb, Recommendation Class IIb, Evidence Category B |
| Cyclophosphamide | Injection/Tablet | Indication | Primary light chain amyloidosis as part of a treatment regimen | Oral or intravenous cyclophosphamide 300 mg/m2 on days 1, 8, 15, 22 of each cycle, combined with bortezomib, for up to 6 cycles | Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. (Palladini et al., 2020) | Not listed in Micromedex |
| Daratumumab | Injection | Indication | Primary light chain amyloidosis | Intravenous administration of 16 mg/kg on days 1, 8, 15, 22 of the first two cycles, then once every week for cycles 3–6, and then once every 4 weeks thereafter | 1. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. (Roussel et al., 2020) 2. Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria. (Kimmich et al., 2020) | Effectiveness Class IIa, Recommendation Class IIa, Evidence Category B |
| Dexamethasone | Injection/Tablet | Indication | Primary light chain amyloidosis | Oral or intravenous dexamethasone 40 mg weekly (starting dose), for up to 6 cycles | Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. (Palladini et al., 2020) | Not listed in Micromedex |
| Pomalidomide | Capsule | Indication | Primary light chain amyloidosis as part of a treatment regimen | Used in combination with dexamethasone, 4 mg daily | A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. (Palladini et al., 2017) | Effectiveness Class IIa, Recommendation Class IIb, Evidence Category B |
Off-label drug usage catalog for treating primary light chain amyloidosis.
3.10 Off-label drug use for treating sickle cell anemia
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.
TABLE 9
| Generic name | Dosage form | Off-label type | Off-label content | Specific usage | Evidence and references | Evidence level |
|---|---|---|---|---|---|---|
| Hydroxyurea | Tablet | Indication | Sickle cell anemia (moderate to severe) | Start with a daily oral dose of 15 mg/kg, increase by 5 mg/kg/day every 12 weeks up to a maximum of 35 mg/kg/day based on blood cell count | FDA approved (Product Information: DROXIAR oral capsules, hydroxyurea oral capsules,, 2015) | Effectiveness Class IIa, Recommendation Class IIa, Evidence Category B |
| L-glutamine | Capsule | Indication | Sickle cell anemia | For weight below 30 kg, 15 g twice daily; for weight 30–65 kg, 10 g twice daily; for weight above 65 kg, 15 g twice daily | FDA approved (Product Information: ENDARITM oral powder, L-glutamine oral powder., 2017) | Effectiveness Class I, Recommendation Class I, Evidence Category B |
Off-label drug usage catalog for treating sickle cell anemia.
3.11 Off-label drug use for treating eczema, thrombocytopenia, and immunodeficiency syndrome (Wiskott-Aldrich syndrome)
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.
TABLE 10
| Generic name | Form | Off-label type | Off-label content | Specific usage | Evidence base and references | Evidence level |
|---|---|---|---|---|---|---|
| Immunoglobulin | Injection | Indication | Eczema-Thrombocytopenia-Immunodeficiency Syndrome | Intravenous infusion, used as a replacement therapy to improve immune function | 1. FDA approved (Product Information: CUTAQUIGTM subcutaneous solution, immune globulin subcutaneous human-hipp subcutaneous solution., 2021) 2. The Wiskott-Aldrich syndrome (Hans and Thrasher, 2006) | Effectiveness Class IIa, Recommendation Class IIa, Evidence Category B |
| Prednisone | Tablet | Indication | Eczema-Thrombocytopenia-Immunodeficiency Syndrome | Used for short-term systemic treatment of eczema | The Wiskott-Aldrich syndrome. (Hans and Thrasher, 2006) | Not listed in Micromedex |
| Recombinant Thrombopoietin | Injection | Indication | Eczema-Thrombocytopenia-Immunodeficiency Syndrome | Used as an adjunctive treatment for thrombocytopenia | Thrombopoietin receptor agonists in hereditary thrombocytopenias.(Rodeghiero et al., 2018) | Not listed in Micromedex |
| Eltrombopag | Tablet | Indication | Eczema-Thrombocytopenia-Immunodeficiency Syndrome | Oral daily dose of Eltrombopag (9–75 mg), adjust dose to maintain platelet count >50 × 109/L | 1. Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia.(Gerrits et al., 2015) 2. Thrombopoietin receptor agonists in hereditary thrombocytopenias (Rodeghiero et al., 2018) | Not listed in Micromedex |
| Romiplostim | Injection | Indication | Eczema-Thrombocytopenia-Immunodeficiency Syndrome | Used for treatment of Eczema-Thrombocytopenia-Immunodeficiency Syndrome when Eltrombopag is ineffective | Thrombopoietin receptor agonists in hereditary thrombocytopenias (Rodeghiero et al., 2018) | Not listed in Micromedex |
| Busulfan | Injection/Tablet | Indication | Eczema-Thrombocytopenia-Immunodeficiency Syndrome in combination with immunosuppressive treatment | 2 mg/kg/day for 4 consecutive days | Reconstitution of normal megakaryocytopoiesis and immunologic functions in Wiskott-Aldrich syndrome by marrow transplantation following myeloablation and immunosuppression with busulfan and cyclophosphamide (Kapoor et al., 1981) | Not listed in Micromedex |
| Cyclophosphamide | Injection/Tablet | Indication | Eczema-Thrombocytopenia-Immunodeficiency Syndrome in combination with immunosuppressive treatment | 50 mg/kg/day for 4 consecutive days | Reconstitution of normal megakaryocytopoiesis and immunologic functions in Wiskott-Aldrich syndrome by marrow transplantation following myeloablation and immunosuppression with busulfan and cyclophosphamide (Kapoor et al., 1981) | Not listed in Micromedex |
Off-label drug usage catalog for treating eczema, thrombocytopenia, and immunodeficiency syndrome.
4 Conclusion
This consensus standardizes the management of off-label drug use for rare hematologic diseases, helping medical institutions develop lists of off-label drugs for rare diseases, promoting rational drug use, and addressing the diagnostic and treatment needs of patients with rare diseases. It also contributes to exploring and establishing an evaluation and management system for off-label drug use in rare diseases.
Statements
Author contributions
BxZ: Writing–review and editing, Writing–original draft. XZ: Writing–original draft, Investigation. PZ: Writing–review and editing, Methodology, Investigation. BZ: Writing–review and editing. XF: Writing–review and editing. JC: Writing–review and editing. LC: Writing–review and editing. YC: Writing–review and editing. LH: Writing–review and editing. JaS: Writing–review and editing. SC: Writing–review and editing. YZ: Writing–review and editing. GL: Writing–review and editing. BJ: Writing–review and editing. JW: Writing–review and editing. WF: Writing–review and editing. ML: Writing–review and editing. YJ: Writing–review and editing. TL: Writing–review and editing. XM: Writing–review and editing. JW: Writing–review and editing. HW: Writing–review and editing. HZ: Writing–review and editing. ZcZ: Writing–review and editing. ZhZ: Writing–review and editing, Project administration, Methodology. JnS: Writing–review and editing, Project administration. YL: Writing–review and editing, Project administration.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2024.1477550/full#supplementary-material
References
1
ArzooK.SadeghiS.PullarkatV. (2001). Pamidronate for bone pain from osteolytic lesions in Langerhans'-cell histiocytosis. N. Engl. J. Med.345 (3), 225. 10.1056/NEJM200107193450318
2
BaumgartnerI.HochstetterA.BaumertB.LuetolfU.FollathF. (1997). Langerhans'-cell histiocytosis in adults. Med. Pediatr. Oncol.28 (1), 9–14. 10.1002/(sici)1096-911x(199701)28:1<9::aid-mpo3>3.0.co;2-p
3
BlundellM. P.WorthA.BoumaG.ThrasherA. J. (2010). The Wiskott-Aldrich syndrome: the actin cytoskeleton and immune cell function. Dis. Markers29 (3-4), 157–175. 10.3233/DMA-2010-0735
4
BrodskyR. A. (2014). Paroxysmal nocturnal hemoglobinuria. Blood124 (18), 2804–2811. 10.1182/blood-2014-02-522128
5
CaiQ. Q.WangC.CaoX. X.CaiH.ZhouD. B.LiJ. (2015). Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome. Eur. J. Haematol.95 (4), 325–330. 10.1111/ejh.12492
6
CheR.ZhangJ.NepalM.HanB.FeiP. (2018). Multifaceted Fanconi anemia signaling. Trends Genet.34 (3), 171–183. 10.1016/j.tig.2017.11.006
7
ChenY.YangK.MarušicA.QaseemA.MeerpohlJ. J.FlottorpS.et al (2017). A reporting tool for practice guidelines in Health care: the RIGHT statement. Ann. Intern. Med.166, 128–132. 10.7326/M16-1565
8
Chinese Society of Hematology, Red Blood Cell Disease (Anemia) Study Group (2020). Expert consensus on the diagnosis and treatment of porphyria in China. Chin. Med. J.100 (14), 1051–1056. 10.3760/cma.j.cn112137-20200219-00349
9
DaiJ.CaoX. (2023). Research progress in the treatment of adult Langerhans cell histiocytosis. Chin. J. Intern. Med.62 (1), 97–102. 10.3760/cma.j.cn112138-20220106-00014
10
DhallG.FinlayJ. L.DunkelI. J.EttingerL. J.KellieS. J.AllenJ. C.et al (2008). Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr. Blood Cancer50 (1), 72–79. 10.1002/pbc.21225
11
DiamondE. L.DagnaL.HymanD. M.CavalliG.JankuF.Estrada-VerasJ.et al (2014). Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease. Blood124 (4), 483–492. 10.1182/blood-2014-03-561381
12
DispenzieriA. (2021). POEMS syndrome: 2021 Update on diagnosis, risk-stratification, and management. Am. J. Hematol.96 (7), 872–888. 10.1002/ajh.26240
13
FarranR. P.ZaretskiE.EgelerR. M. (2001). Treatment of Langerhans cell histiocytosis with pamidronate. J. Pediatr. Hematol. Oncol.23 (1), 54–56. 10.1097/00043426-200101000-00013
14
GavriatopoulouM.MustoP.CaersJ.MerliniG.KastritisE.van de DonkN.et al (2018). European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. Leukemia32 (9), 1883–1898. 10.1038/s41375-018-0209-7
15
GerritsA. J.LevenE. A.FrelingerA. L. 3rdBrigstockeS. L.Berny-LangM. A.MitchellW. B.et al (2015). Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia. Blood126 (11), 1367–1378. 10.1182/blood-2014-09-602573
16
GianfredaD.NicastroM.GalettiM.AlbericiF.CorradiD.BecchiG.et al (2015). Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial. Blood126 (10), 1163–1171. 10.1182/blood-2015-01-620377
17
Guangdong Pharmaceutical Association (2023). Notice on the release of the Off-Label drug use catalog. Available at: http://www.sinopharmacy.com.cn/notification/2797.html (Guangdong Pharmaceutical Association [2023] No. 72). Guangzhou: Guangdong Pharmaceutical Association, 2023-07-04 [accessed on 2023-07-04].
18
HansD. O.ThrasherA. J. (2006). The Wiskott-Aldrich syndrome. J. Allergy Clin. Immunol.117 (4), 725–738. quiz 739. 10.1016/j.jaci.2006.02.005
19
HarocheJ.Cohen-AubartF.AmouraZ. (2020). Erdheim-Chester disease. Blood135 (16), 1311–1318. 10.1182/blood.2019002766
20
HeH.FuW.DuJ.JiangH.HouJ. (2018). Successful treatment of newly diagnosed POEMS syndrome with reduced-dose bortezomib based regimen. Br. J. Haematol.181 (1), 126–128. 10.1111/bjh.14497
21
Hematology Committee of Chinese Medical Association, Hematological Oncology Committee of China Anti-Cancer Association, China Castleman Disease Network (CCDN) (2021). The consensus of the diagnosis and treatment of Castleman disease in China (2021). Chin. J. Hematol.42 (7), 529–534. 10.3760/cma.j.issn.0253-2727.2021.07.001
22
Hematology Oncology Committee of China Anti-Cancer Association, Leukemia & Lymphoma Group Society of Hematology at Chinese Medical Association (2016). The consensus of the diagnosis and treatment of primary light chain amyloidosis in China (2016 version). Chin. J. Hematol.37 (9), 742–746. 10.3760/cma.j.issn.0253-2727.2016.09.003
23
HenterJ. I.KarlénJ.CalmingU.BernstrandC.AnderssonU.FadeelB. (2001). Successful treatment of Langerhans'-cell histiocytosis with etanercept. N. Engl. J. Med.345 (21), 1577–1578. 10.1056/NEJM200111223452118
24
HoegerP. H.NanduriV. R.HarperJ. I.AthertonD. A.PritchardJ. (2000). Long term follow up of topical mustine treatment for cutaneous Langerhans cell histiocytosis. Arch. Dis. Child.82, 483–487. 10.1136/adc.82.6.483
25
HuangX.WangQ.ChenW.ZengC.ChenZ.GongD.et al (2014). Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med.12 (2), 2. 10.1186/1741-7015-12-2
26
IshiiE.MatsuzakiA.OkamuraJ.InoueT.KajiwaraM.UozumiT.et al (1992). Treatment of Langerhans cell histiocytosis in children with etoposide. Am. J. Clin. Oncol.15, 515–517. 10.1097/00000421-199212000-00011
27
KapoorN.KirkpatrickD.BlaeseR. M.OleskeJ.HilgartnerM. H.ChagantiR. S.et al (1981). Reconstitution of normal megakaryocytopoiesis and immunologic functions in Wiskott-Aldrich syndrome by marrow transplantation following myeloablation and immunosuppression with busulfan and cyclophosphamide. Blood57 (4), 692–696. 10.1182/blood.v57.4.692.692
28
KerstenM. J.LangeR.SmeetsM. E.VreugdenhilG.RoozendaalK. J.LameijerW.et al (1996). Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multi-center trial. Ann. Hematol.73, 247–252. 10.1007/s002770050236
29
KhouriJ.NakashimaM.WongS. (2021). Update on the diagnosis and treatment of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome: a review. JAMA Oncol.7 (9), 1383–1391. 10.1001/jamaoncol.2021.0586
30
KimmichC. R.TerzerT.BennerA.DittrichT.VeelkenK.CarpinteiroA.et al (2020). Daratumumab for systemic AL amyloidosis: prognostic factors and adverse outcome with nephrotic-range albuminuria. Blood135 (18), 1517–1530. 10.1182/blood.2019003633
31
KorholzD.JanbenG.GobelU. (1997). Treatment of relapsed Langerhans cell histiocytosis by cyclosporin A combined with etoposide and prednisone. Pediatr. Hematol. Oncol.14, 443–449. 10.3109/08880019709028774
32
KulkarniG. B.MahadevanA.TalyA. B.YashaT. C.SeshagiriK. S.NaliniA.et al (2011). Clinicopathological profile of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome. J. Clin. Neurosci.18 (3), 356–360. 10.1016/j.jocn.2010.07.124
33
KyleR. A.LinosA.BeardC. M.LinkeR. P.GertzM. A.O'FallonW. M.et al (1992). Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989 [see comments]. Blood79 (7), 1817–1822. 10.1182/blood.v79.7.1817.1817
34
LiJ.ZhouD. B.HuangZ.JiaoL.DuanM. H.ZhangW.et al (2011). Clinical characteristics and long-term outcome of patients with POEMS syndrome in China. Ann. Hematol.90 (7), 819–826. 10.1007/s00277-010-1149-0
35
MahmoudH. H.WangW. C.MurphyS. B. (1991). Cyclosporine therapy for advanced Langerhans cell histiocytosis [see comments]. Blood77, 721–725. 10.1182/blood.v77.4.721.bloodjournal774721
36
MassaadM. J.RameshN.GehaR. S. (2013). Wiskott-Aldrich syndrome: a comprehensive review. Ann. N. Y. Acad. Sci.1285, 26–43. 10.1111/nyas.12049
37
MeraiH.CollasD.BhagatA.MandaliaU. (2020). Erdheim-Chester disease: a case report and review of the literature. J. Clin. Imaging Sci.10, 37. 10.25259/JCIS_68_2020
38
MisawaS.SatoY.KatayamaK.NagashimaK.AoyagiR.SekiguchiY.et al (2016). Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol.15 (11), 1129–1137. 10.1016/S1474-4422(16)30157-0
39
MoreauP.MilpiedN.de FaucalP.PetitT.HerbouillerP.BatailleR.et al (1996). High-dose melphalan and autologous bone marrow transplantation for systemic AL amyloidosis with cardiac involvement [letter]. Blood87, 3063–3064. 10.1182/blood.v87.7.3063.bloodjournal8773063
40
NordmannT. M.JuenglingF. D.RecherM.BergerC. T.KalbermattenD.WickiA.et al (2017). Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both BRAF and KRAS mutations. Blood129 (7), 879–882. 10.1182/blood-2016-09-740217
41
NozzaA.TerenghiF.GalliaF.AdamiF.BrianiC.MerliniG.et al (2017). Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective, open-label trial. Br. J. Haematol.179 (5), 748–755. 10.1111/bjh.14966
42
PalladiniG.KastritisE.MaurerM. S.ZonderJ.MinnemaM. C.WechalekarA. D.et al (2020). Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood136 (1), 71–80. 10.1182/blood.2019004460
43
PalladiniG.MilaniP.FoliA.BassetM.RussoF.PerliniS.et al (2017). A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood129 (15), 2120–2123. 10.1182/blood-2016-12-756528
44
PalladiniG.RussoP.FoliA.MilaniP.LavatelliF.ObiciL.et al (2012). Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann. Hematol.91 (1), 89–92. 10.1007/s00277-011-1244-x
45
PalladiniG.RussoP.MilaniP.FoliA.LavatelliF.NuvoloneM.et al (2013). A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica98 (3), 433–436. 10.3324/haematol.2012.073593
46
PayneA. B.MehalJ. M.ChapmanC.HaberlingD. L.RichardsonL. C.BeanC. J.et al (2020). Trends in sickle cell disease-related mortality in the United States, 1979 to 2017. Ann. Emerg. Med.76 (3S), S28-S36–S36. 10.1016/j.annemergmed.2020.08.009
47
Physician Law on Doctors of the People’s Republic of China (2021). The national People’s congress of the People’s Republic of China. Available at: http://www.npc.gov.cn/npc/c2/c30834/202108/t20210820_313104.html.
48
Product Information: HEMLIBRA(R) subcutaneous injection, emicizumab-kxwh subcutaneous injection (2021). South San Francisco, CA: Genentech Inc per FDA.
49
Product Information: CUTAQUIG(TM) subcutaneous solution (2021). Immune globulin subcutaneous (human)-hipp subcutaneous solution. Pfizer Labs (per FDA). N. Y. Available at: https://www.fda.gov/media/119234/download.
50
Product Information: CYKLOKAPRON(R) intravenous injection (2020). Tranexamic acid intravenous injection. New York, NY: Pharmacia & Upjohn Company per FDA.
51
Product Information: DROXIA(R) oral capsules (2015). Hydroxyurea oral capsules. Princeton, NJ: Bristol-Myers Squibb Company per FDA. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-hydroxyurea-treatment-pediatric-patients-sickle-cell-anemia.
52
Product Information: ENDARI(TM) oral powder (2017). L-glutamine oral powder. Torrance, CA: Emmaus Medical, Inc per FDA. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approved-l-glutamine-powder-treatment-sickle-cell-disease.
53
Product Information: vinblastine sulfate intravenous injection, vinblastine sulfate intravenous injection (2008). APP pharmaceuticals. Schaumburg, IL: LLC.
54
Product Information: ZELBORAF(R) oral tablets, vemurafenib oral tablets (2017). South San Francisco, CA: Genentech USA, Inc per FDA. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429-s012lbl.pdf.
55
ReesD. C.WilliamsT. N.GladwinM. T. (2010). Sickle-cell disease. Lancet376 (9757), 2018–2031. 10.1016/S0140-6736(10)61029-X
56
RodeghieroF.PecciA.BalduiniC. L. (2018). Thrombopoietin receptor agonists in hereditary thrombocytopenias. J. Thromb. Haemost.16 (9), 1700–1710. 10.1111/jth.14217
57
Rodriguez-GalindoC.KellyP.JengM.PresburyG. G.RiemanM.WangW. (2002). Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine. Am. J. Hematol.69, 179–184. 10.1002/ajh.10053
58
RousselM.MerliniG.ChevretS.ArnulfB.StoppaA. M.PerrotA.et al (2020). A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood135 (18), 1531–1540. 10.1182/blood.2019004369
59
SeldinD. C.ChoufaniE. B.DemberL. M.WiesmanJ. F.BerkJ. L.FalkR. H.et al (2003). Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis. Clin. Lymphoma3 (4), 241–246. 10.3816/clm.2003.n.005
60
SoubrierM. J.DubostJ. J.SauvezieB. J. (1994). POEMS syndrome: a study of 25 cases and a review of the literature. French Study Group on POEMS syndrome. Am. J. Med.97 (6), 543–553. 10.1016/0002-9343(94)90350-6
61
StineK. C.SaylorsR. L.SaccenteS.McClainK. L.BectonD. L. (2004). Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr. Blood Cancer43 (1), 81–84. 10.1002/pbc.20053
62
T/GDPA 1-2021, GuangDong Pharmaceutical Association. (2021) The specification of evidence-base pharmaceutical evaluation method for off-label drug use.
63
van RheeF.OksenhendlerE.SrkalovicG.VoorheesP.LimM.DispenzieriA.et al (2020). International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease. Blood Adv.4 (23), 6039–6050. 10.1182/bloodadvances.2020003334
64
van RheeF.VoorheesP.DispenzieriA.FossåA.SrkalovicG.IdeM.et al (2018). International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood32 (20), 2115–2124. 10.1182/blood-2018-07-862334
65
VelazquezI.AlterB. P. (2004). Androgens and liver tumors: fanconi's anemia and non-Fanconi's conditions. Am. J. Hematol.77 (3), 257–267. 10.1002/ajh.20183
66
VianaM. B.OliveiraB. M.SilvaC. M.Rios LeiteV. H. (1991). Etoposide in the treatment of six children with Langerhans cell histiocytosis (histiocytosis X). Med. Ped Oncol.19, 289–294. 10.1002/mpo.2950190414
67
WangJ. N.LiuT.ZhaoA. L.PanB. J.SunJ.LiJ.et al (2022). Phase 2 study of oral thalidomide-cyclophosphamide-dexamethasone for recurrent/refractory adult Langerhans cell histiocytosis. Leukemia36 (6), 1619–1624. 10.1038/s41375-022-01555-8
68
WeberN.MolleeP.AugustsonB.BrownR.CatleyL.GibsonJ.et al (2015). Management of systemic AL amyloidosis: recommendations of the myeloma foundation of Australia medical and scientific advisory group. Intern Med. J.45 (4), 371–382. 10.1111/imj.12566
69
WechalekarA. D.GillmoreJ. D.BirdJ.CavenaghJ.HawkinsS.KazmiM.et al (2015). Guidelines on the management of AL amyloidosis. Br. J. Haematol.168 (2), 186–206. 10.1111/bjh.13155
70
Word Health Organization (2014). WHO Handbook for guideline development. 2nd ed. Geneva, Switzerland: WHO.
71
XueF.DaiJ.ChenL. X.LiuW.ZhangH. Q.WuR. H.et al (2023). Report on diagnosis and treatment of hemophilia in China 2023. J. Diagn. Concepts Pract.22 (02), 89–115. 10.16150/j.1671-2870.2023.02.001
72
XueF.YangR. C. (2022). Establishment and evolution of China national hemophilia registry. J. Rare Dis.1 (4), 370–374. 10.12376/j.issn.2097-0501.2022.04.002
73
ZellerB.Storm-MathisenI.SmevikB.LieS. O. (2000). Multisystem Langerhans-cell histiocytosis with life-threatening pulmonary involvement--good response to cyclosporine A. Med. Pediatr. Oncol.35, 438–442. 10.1002/1096-911x(20001001)35:4<438::aid-mpo12>3.0.co;2-4
74
ZhangL.DongY. J.PengH. L.LiH.ZhangM. Z.WangH. H.et al (2023). A national, multicenter, retrospective study of Castleman disease in China implementing CDCN criteria. Lancet Reg. Health West Pac34, 100720. 10.1016/j.lanwpc.2023.100720
Summary
Keywords
rare diseases, hematological disease, off-label drug use, expert consensus, evidence based pharmacy
Citation
Zhao B, Zhou X, Zheng P, Zhang B, Feng X, Chen J, Cai L, Chen Y, He L, Su J, Cheng S, Zeng Y, Li G, Ji B, Wu J, Feng W, Liu M, Jin Y, Liu T, Mo X, Wu J, Wu H, Zhang H, Zheng Z, Zheng Z, Sun J, Li Y and Guangdong Pharmaceutical Association, Hematology Group of Rare Disease Expert Committee of Guangdong Pharmaceutical Association (2024) Expert consensus on the off-label use in China of drugs for rare hematologic diseases (2024 edition). Front. Pharmacol. 15:1477550. doi: 10.3389/fphar.2024.1477550
Received
08 August 2024
Accepted
17 September 2024
Published
22 November 2024
Volume
15 - 2024
Edited by
Shusen Sun, Western New England University, United States
Reviewed by
Hongtao Xiao, University of Electronic Science and Technology of China, China
Quanjun Yang, Shanghai Jiao Tong University, China
Updates
Copyright
© 2024 Zhao, Zhou, Zheng, Zhang, Feng, Chen, Cai, Chen, He, Su, Cheng, Zeng, Li, Ji, Wu, Feng, Liu, Jin, Liu, Mo, Wu, Wu, Zhang, Zheng, Zheng, Sun, Li and Guangdong Pharmaceutical Association, Hematology Group of Rare Disease Expert Committee of Guangdong Pharmaceutical Association.
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*Correspondence: Zhihua Zheng, snownotrace@126.com; Jing Sun, jsun_cn@hotmail.com; Yilei Li, liyilei1975@163.com
†These authors have contributed equally to this work and share first authorship
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