High-dose Chemotherapy with Thiotepa, Busulfan, and Cyclophosphamide Followed by Autologous Stem Cell Transplantation in Central Nervous System Lymphoma

Efficacy of High-dose Chemotherapy with Thiotepa, Busulfan, and Cyclophosphamide Before Autologous Stem Cell Transplantation in Patients with Primary/secondary Central Nervous System Lymphoma

The involvement of the central nervous system (CNS) by non-Hodgkin lymphoma (NHL) has carried a poor prognosis. For both of primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL), high-dose methotrexate (HD- MTX) based chemotherapy and combined modality have significantly improved the previously poor response rates and prognosis. However, in PCNSL, relapse rates have remained high, with only 20% to 30% patients achieving a durable long-term remission after HD-MTX. The combination with whole-brain radiotherapy (WBRT) has resulted in higher disease-free and overall survival rates, but it has also been associated with severe neurotoxicity. Patients with SCNSL fare the worst, typically succumbing to disease within median 2.5 to 4 months with 1-year survival rates of only 25%.

Because of these dismal outcomes, intensification of the high-dose chemotherapy (HDC)with autologous stem cell transplantation (autoSCT) has been explored for PCNSL and SCNSL as salvage treatment in patients with refractory or relapsed disease, and as consolidation after primary chemotherapy, replacing or preceding WBRT. Thiotepa, busulfan, and cyclophosphamide (TBC) have significant penetration of blood-brain barrier as shown in several pharmacokinetic studies. Thus, combination of these 3 agents was proposed as one high-dose chemotherapy regimen to achieve therapeutic concentrations in the lymphoma tissue in chemotherapy sanctuaries, like cerebrospinal fluid (CSF), meninges and eyes. eyes. Several studies have shown promising results and favorable long-term toxicity profiles with this combination. However, the relatively rarity of this tumor precludes rapid completion of large-scale phase III trial and, therefore, our reliance on the results of well-designed phase II trials is critical. Therefore, we evaluate the efficacy and toxicity of thiotepa, bulsulfan, and cyclophosphamide as a conditioning for autologous stem cell transplantation in patients with PCNSL and SCNSL.

Study Overview

• Status: Terminated
• Conditions: Central Nervous System Lymphoma
• Intervention / Treatment: Drug: Thiotepa in conditioning before transplantation

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ∙Patients with histologically confirmed primary central nervous system lymphoma or secondary CNS lymphoma defined as either synchronous CNS involvement of sys- temic NHL or as a site of recurrence in a patient s with a history of systemic NHL

  • Patients who achieved remission after first line chemotherapy and/or WBRT, or who experience relapse of PCNSL/SCNLS.
  • Patients who have not previously received therapy with high high-dose chemotherapy and stem cell transplantatitransplantation.
  • The performance st atus of the patients should be 2 or less by ECOG performance scale.
  • Patients should not have major illness or organ failure incompatible with autologous stem cell transplantation.
• Patients must have adequate hepatic function (serum bilirubin less than 2.0mg/dl, AST and ALT less than three times the upper normal limit)
• Patients must have adequate renal function ( serum creatinin less than 2.0mg/dl)
• Patients must have adequate cardiac function (ejection fraction 45% on echo- cardiogram)
• Patients must have adequate bone marrow function (ANC 1,000/mm 3 and platelet count 75,000/mm 3 ∙ All patients are fully informed about the nature and purpose of this study and informed consent should be given before the start of treatment. All patients should fully understand the right or trial abandon without any disadvantage.

Exclusion Criteria:

• Concurrent history of neoplasm other than CNS lymphoma with life expectancy less than 3 months.
• History of clinically significant cardiac dysfunction (ex. CHF, symptomatic CAD, uncontrolled arrhythmia) or MI within 12 months.
• psychiatric disorders or mental deficiency severe as to make compliance with the treatment unlike, and making informed consent impossible
• significant infection or uncontrolled bleeding
• enrollment of other clinical trials within 4 weeks prior to treatment
• any preexisting medical condition of sufficient severity to prevent full compliance with study
• patient being not willing to or unable to obey study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment arm; Patients with histologically confirmed primary central nervous system lymphoma or secondary CNS lymphoma defined as either synchronous CNS involvement of sys- temic NHL or as a site of recurrence in a patient s with a history of systemic NHL; Patients who achieved remission after first line chemotherapy and/or WBRT, or who experience relapse of PCNSL/SCNLS.; Patients who have not previously received therapy with high high-dose chemotherapy and stem cell transplantatitransplantation.; The performance st atus of the patients should be 2 or less by ECOG performance scale.; Patients should not have major illness or organ failure incompatible with autologous stem cell transplantation.

Drug: Thiotepa in conditioning before transplantation; For patients with ECOG PS 0 or 1 For patients with ECOG PS 0 or 1 and age < 60 years old, conditioning regimen before autologous stem cell transplantation consists of thiotepa, bulsulfan, and cyclophosphamide from day -9. Beginning on day -9 and through day -7, each patient was treated with thiotepa (200mg/m m2 IV per day). On days -6 to -4, patients received bulsulfan (2.7mg/kg IV over 3 hours per day every). Bulsulfan-related seizure prophylaxis was given with levetriacetam (1500mg loading on day -6, 500mg twice daily on days -5 to -3). On days -3 and -2, cyclophosphamide (60mg/kg IV per day) was given given. Patients with ECOG PS 2 or age ≥ 60 years old received bulsulfan (3.2mg/kg IV over 3 hours per day for 2 days) resulting in 8 days regimen.; Other Names: high-dose CTx with TBC, followed by auto-SCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS was calculated from the date of transplantation to the date of disease progression or death from any cause. Patients who were alive without relapse or progression were censored at the time of last contact.	1-year PFS

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS was calculated from the date of transplantation to death from any cause.	through study completion, an average of 1 year
Relapse rate		through study completion, an average of 1 year
Non-relapse mortality (NRM)	NRM was defined as any death without evidence of relapse.	through study completion, an average of 1 year
Toxicity profile		through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Seoul National University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): September 30, 2024
• Study Completion (Actual): September 30, 2024

Study Registration Dates

• First Submitted: September 30, 2024
• First Submitted That Met QC Criteria: October 1, 2024
• First Posted (Actual): October 3, 2024

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: October 1, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: PCNSL; SCNSL; high-dose chemotherapy followed by autoSCT; Thiotepa, Busulfan, Cyclophosphamide
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Thiotepa
• Other Study ID Numbers: C-1503-129-659

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: not determined

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No