This is a prospective, dose-escalation clinical study to evaluate the safety and efficacy of GVM±R in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL).

This is a single-arm, single-center, dose-escalation clinical study to explore the maximum tolerated dose (MTD) of liposomal mitoxantrone hydrochloride when combined with gemcitabine, vinorelbine and/or rituximab (GVM ± R) in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Liposomal mitoxantrone hydrochloride will be given on day 1 at four different doses (16 mg/m2, 18 mg/m2, 20 mg/m2,22 mg/m2) and be combined with gemcitabine, vinorelbine and/or rituximab (rituximab only in CD20+ lymphoma). The dose limited toxicity (DLT) will be evaluated after the first cycle of therapy. A maximum of 6 cycles of therapy are planned.

Inclusion Criteria:

1. Subjects fully understand and voluntarily participate in this study and sign the informed consent
2. Age ≥18, ≤70years, no gender limitation
3. Expected survival ≥ 3 months;
4. Histologically confirmed diagnosis of aggressive NHL.
5. Subjects with relapsed or refractory NHL. Relapsed disease is defined as the disease relapsing after CR or PR, and the duration of prior response is more than 6 months. Refractory disease can be confirmed if any of the following conditions are met: 1) no PR or CR has been obtained after previous treatment; 2) CR / PR was achieved after prior therapy, but recurred within 6 months; 3) Recurrence after hematopoietic stem cell transplantation.
6. Subjects must have at least one evaluable or measurable lesion per lugano2014 criteria: for lymph node lesions, the length and diameter should be > 1.5cm; For non-lymph node lesions, the length and diameter should be > 1.0cm;
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) : 0-1
8. The following baseline laboratory criteria are required: Absolute neutrophil count (ANC) ≥1.5×109/L, Platelet count (PLT) ≥75×109/ L, Hemoglobin(HB)≥ 80g/L, Total bilirubin (TBIL) ≤1.5X upper limit of normal (ULN), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5X ULN, Serum creatinine (Scr) ≤1.5X ULN.

Exclusion Criteria:

1. The subject had previously received any of the following anti-tumor treatments:

   1. Subjects who have been treated with mitoxantrone or mitoxantrone liposomes;
   2. Previously received doxorubicin or other anthracycline treatment, and the total cumulative dose of doxorubicin was more than 360 mg/m2 (1 mg doxorubicin equivalent to 2 mg epirubicin);
   3. Subjects who received anti-tumor treatment (including chemotherapy, targeted therapy, glucocorticoid, traditional Chinese medicine with anti-tumor activity, etc.) or participated in other clinical trials and received trial drugs within 4 weeks before the first administration of the study drugs;
   4. Subjects who received autologous hematopoietic stem cell transplantation or allogeneic hematopoietic stem cell transplantation within 100 days of the first administration of study drugs;

2. Hypersensitivity to any study drug or its components;

3. Uncontrolled systemic diseases (such as active infection, uncontrolled hypertension, diabetes, etc.)

4. Heart function and disease meet one of the following conditions:

   1. Long QTc syndrome or QTc interval > 480 ms;
   2. Complete left bundle branch block, grade II or III atrioventricular block;
   3. Serious and uncontrolled arrhythmias requiring drug treatment;
   4. New York Heart Association grade ≥ III;
   5. Cardiac ejection fraction (LVEF)# 50%;
   6. A history of myocardial infarction, unstable angina pectoris, severe unstable ventricular arrhythmia or any other arrhythmia requiring treatment, a history of clinically serious pericardial disease, or ECG evidence of acute ischemia or active conduction system abnormalities within 6 months before recruitment.

9. Hepatitis B and hepatitis C active infection (defined as hepatitis B virus surface antigen positive and hepatitis B virus DNA higher than 1x103 copy/mL; hepatitis C virus RNA high than 1x103 copy/mL) 10. Human immunodeficiency virus (HIV) infection (defined as HIV antibody positive) 11. Patients with other malignant tumors, except for effectively controlled non- melanoma skin basal cell carcinoma, breast/cervical carcinoma in situ or other tumors without treatment during the past 5 years. 12. Pregnant and lactating women and patients of childbearing age who are unwilling to take contraceptive measures; 13. Unsuitable subjects for this study determined by the investigator.