High-dose Cyclophosphamide Induction Therapy in Adult Patients With HLH

shifeng Lou (Other)
Overall Status
CT.gov ID

Study Details

Study Description

Brief Summary

Adult secondary HLH involves tumors, autoimmune diseases and other causes in addition to infection,Infectious factors, theoretically need different treatment methods for different etiology. But adult HLH itself disease .The situation progresses ferociously, which can cause organ damage and blood coagulation disorder and endanger life quickly, with early mortality (30days).It can be more than 50%. On the other hand, although diagnostic techniques have improved significantly, identifying the cause is still costly Time, such as 1-2 weeks for the pathological diagnosis of lymphoma, leads to more patients losing further treatment due to early death.

The opportunity to heal. Therefore, it is important to explore effective induction therapy for adult HLH. In the majority ,Early (30-day) mortality was as high as 40% after cardiac induction using HLH2004 or CHOP induction. HLH, on the other hand, usually requires prompt treatment before the cause is established. Due to a specific infection HLH can benefit from anti-infective therapy. Therefore, it is necessary to explore more effective induction therapy for adult non-infective HLH.It has very important clinical significance. Adult secondary HLH has the common features of a large number of T cell proliferation and activation and a significant reduction of NK cells, in which the central link is a large number of T cells proliferation and secretion of cytokines, which can be used as induction therapy.Common target is also the pathological basis for designing unified induction scheme. Cyclophosphamide is a commonly used alkylated chemotherapy drug,It's also an important immunosuppressant. Based on the treatment of regenerative disorders anemia, allogeneic hematopoietic stem cell transplantation prevention.Experience with Plant versus Host disease (GVHD) has shown that the use of cyclophosphamide exceeds a total dose of 25mg/day,Two days can effectively kill CD8+ or CD4+T cells, and the maximum tolerated dose of this drug in humans exceeds 50mg/kg/day for two days. Aiming at the central link of adult HLH pathogenesis, The investigators designed for the first time to use a large dose of cyclophosphamide (25mg-50mg/kg/day 2days) to inhibit the activation of T cells, inhibit the production of cytokines and block the development mechanism of HLH. This study intends to conduct a randomized controlled study, with HLH2004 scheme as the control, and the observation is large efficacy and safety of dose cyclophosphamide in induction therapy of non-infective adult HLH in order to create a new induction Treatment plan.

Condition or Disease Intervention/Treatment Phase

Study Design

Study Type:
Anticipated Enrollment :
160 participants
Intervention Model:
Parallel Assignment
None (Open Label)
Primary Purpose:
Official Title:
A Randomized Controlled Study of High-dose Cyclophosphamide Induction Therapy in Adult Patients With HLH
Actual Study Start Date :
Apr 20, 2023
Anticipated Primary Completion Date :
Apr 20, 2026
Anticipated Study Completion Date :
May 20, 2027

Arms and Interventions

Arm Intervention/Treatment
Experimental: CTX group

Drug: cyclophosphamide
cyclophosphamide 40mg/kg iv qd x 2days (day 1 and 2);

Drug: Dexamethasone
Dexamethasone: 10 mg/m2/day, week 1 to 2; 5 mg/m2/d for the 3rd to 4th week; 2.5 mg/m2/ day at week 5-6.

Active Comparator: Normal treatment group

Drug: VP-16
VP-16:150 mg/m2, twice a week, 1-2 weeks; 150mg/m2, once a week for the 3rd to 6th week.

Drug: Dexamethasone
Dexamethasone: 10 mg/m2/day, week 1 to 2; 5 mg/m2/d for the 3rd to 4th week; 2.5 mg/m2/ day at week 5-6.

Drug: Cyclosporine (CSA)
Cyclosporine (CSA) 100mg Bid, week 1 to 6 (dosed according to 2004 version).

Outcome Measures

Primary Outcome Measures

  1. complete response rate [up to 30days]

    Efficacy evaluation measures included serum sCD25, ferritin, blood count, triglyceride, blood-phagocytosis, and consciousness level (CNS HLH) returning to normal range

  2. Near complete response rate [up to 30days]

    Blood routine red blood cells, white blood cells, platelets returned to normal + other laboratory indicators improved by 50%

Secondary Outcome Measures

  1. partial complete response rate [up to 30days]

    The antipyretic time, liver function, cytokine concentration, blood image recovery time and other indicators were better than the control group

  2. Single improvement degree among 8 indicators of diagnostic criteria [up to 30days]

    Single improvement degree among 8 indicators of diagnostic criteria

  3. 30-day mortality rate [up to 30days]

    30-day mortality rate

  4. Antipyretic time [up to 30days]

    Body temperature is back in the normal range

  5. Invalid (NR) : CR and nCR are not satisfied, or one of the following conditions occurs [up to 30days]

    The body temperature did not decrease for three consecutive days, and secondary bacterial or fungal infection could be excluded. Or continuous deterioration of liver function; IL-2R and ferritin levels increased continuously. Coagulation dysfunction continues to worsen.

Eligibility Criteria


Ages Eligible for Study:
18 Years to 65 Years
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Inclusion Criteria:
  1. Age range from 18 to 65 years old (including the critical value), gender is not limited;

  2. According to the diagnostic criteria of HLH-2004, HLH can be diagnosed if any of the following two criteria are met:

  3. Molecular diagnosis is consistent with HLH: Currently known HLH related pathogenic genes exist, such as PRF1, UNC13D, STX11, STXBP2, Rab27a, LYST, SH2D1A, BIRC4, ITK, AP3β1, MAGT1, CD27 and other pathological mutations.

  4. Meet 5 or more of the following 8 indicators:

  • Fever: body temperature > 38.5 ℃, continuous > 7 d; ② Splenomegaly;

  • Hemocytopenia (involving two or three peripheral blood lines) : hemoglobin < 90 g/L (< 4 weeks infant, hemoglobin < 100 g/L), platelet < 100×109/L, neutrophils < 1.0×109/L and not caused by reduced hematopoietic function of bone marrow; ④ High triglyceride (TG) sepsis and/or low fibrinogenemia: triglyceride > 3 mmol/L or 3 standard deviations above the same age, fibrinogen < 1.5g /L or less than 3 standard deviations for the same age; (5) Hematophagy was found in bone marrow, spleen, liver or lymph nodes;

  • The activity of NK cells is decreased or absent;

⑦ Serum ferritin increase: ferritin ≥500 μg/L; Elevated sCD25 (soluble interleukin-2 receptor). (3) Those who can understand the research content, agree to comply with the research plan, and voluntarily sign the informed consent.

Exclusion Criteria:
  1. HLH caused by treatable infectious causes (such as bacteria, fungi, viruses (except Epstein-Barr virus), protozoa, etc.);

  2. Have a history of allergy or contraindications to the drugs involved in the program;

  3. Organ damage caused by long-term chronic diseases;

  4. Extreme physical weakness, unstable vital signs and inability to tolerate large doses of cyclophosphamide;

  5. Severe and/or uncontrolled co-morbidivities (e.g., uncontrolled diabetes, pulmonary hypertension, etc.) that the investigator believes may pose an unacceptable safety risk or interfere with protocol compliance;

  6. Mental instability or history of severe mental illness

  7. Other factors determined by the researcher that subjects are not suitable to participate in this study.

Contacts and Locations


Site City State Country Postal Code
1 The Second affiliated Hosptial of Chongqing medical University Chongqing China

Sponsors and Collaborators

  • shifeng Lou


  • Study Director: Qing Wen, doctor, Hematology Medical Center, the Second Affiliated Hospital of PLA Army Medical University
  • Study Director: Huaer Shu, bachelor, Chongqing Kaizhou District People's Hospital
  • Study Director: Hongbin Zhang, doctor, First Affiliated Hospital of Chongqing Medical University
  • Study Director: Jinglong Lv, master, Three Gorges Central Hospital Affiliated to Chongqing University
  • Study Director: Zhangqin luo, bachelor, Yongchuan Hospital affiliated to Chongqing Medical University
  • Study Director: Liang Fang, master, Chongqing Ninth People's Hospital
  • Study Director: Yizhi Xu, doctor, People's Hospital of Chongqing
  • Study Director: Zailiang Yang, doctor, Fuling Hospital affiliated to Chongqing University

Study Documents (Full-Text)

None provided.

More Information


None provided.
Responsible Party:
shifeng Lou, Director, The Second Affiliated Hospital of Chongqing Medical University
ClinicalTrials.gov Identifier:
Other Study ID Numbers:
  • XYNK 04
First Posted:
Jul 7, 2023
Last Update Posted:
Jul 7, 2023
Last Verified:
Jun 1, 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:
Studies a U.S. FDA-regulated Drug Product:
Studies a U.S. FDA-regulated Device Product:
Product Manufactured in and Exported from the U.S.:
Keywords provided by shifeng Lou, Director, The Second Affiliated Hospital of Chongqing Medical University
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jul 7, 2023