Relapsed Non-Hodgkin-Lymphoma Clinical Trial
Official title:
Eine Phase II Studie Zur Beurteilung Der Wirksamkeit Von Rituximab in Der Salvage- Und Hochdosistherapie Mit Autologer Stammzelltransplantation Bei Patienten Mit B-Zell-Non-Hodgkin-Lymphom
The investigator prospectively evaluated the combination of Rituximab and Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by high dose therapy in patients with relapsed/refractory aggressive and indolent lymphoma.
This study was a prospective, open label, single arm multicenter phase II study. It was
approved by the ethics committees of the participating centers, and all regulatory issues
and the principles of GCP were followed. The study was initiated in 2002, and recruitment
closed in 2006. Final data analysis was performed in 3/2013. The trial had been registered
at the clinical trial database of the CIMT consortium The overall treatment plan in brief,
eligible patients were treated with two cycles of R-DexaBEAM in a 3-4 week interval, and
stem cell mobilization was scheduled after the second cycle. Mobilization after the first
cycle was allowed if the patient had received extensive prior therapy and if no evidence of
BM-involvement was found. HDT was scheduled within 4-8 weeks after the last R-DexaBEAM cycle
in patients achieving at least PR.
Protocols: The applied chemotherapy protocols were as follows: The
salvage/mobilization-regimen consisted of R-DexaBEAM: Rituximab 375mg/m² d1, dexamethasone
24 mg t.i.d p.o., d 1-10; BCNU 60mg/m² i.v., d 2; etoposide 75mg/m² i.v., d 4-7; cytarabin
200mg/m² b.i.d i.v., d 4-7 in 2 doses; melphalan 20mg/m² i.v., d3. For high dose
radio/chemotherapy, two different conditioning regimens were defined in the protocol:
chemo-radiotherapy R-TBI/Cy consisted of Rituximab 375mg/m² i.v. d -7, -2, fractionated
total body irradiation with 12 Gy, d -6 to -4; and cyclophosphamide 60 mg/kgbw i.v., day -3
to -2.
The chemotherapy protocol used for conditioning was R-BEAM: Rituximab 375mg/m² i.v. d -8,
-2, BCNU 300mg/m² i.v., d -7; cytarabin 400mg/m² b.i.d. i.v., d -6 to -3; etoposide 200mg/m²
i.v. b.i.d., d -6 to -3; melphalan 140mg/m² i.v., d -2.
Stem cell mobilization: Following mobilization chemotherapy, stem cells were collected after
G-CSF stimulation (5-10µg/kg bw/d, starting on day 11 after R-DexaBEAM) using standard
apheresis procedures, and stem cells were processed and cryopreserved according to local
standards. A minimum number of 2x106/kgbw CD34 positive cells were required for the conduct
of high dose therapy.
Autologous stem cell transfusion: For stem cell rescue after HDT, at least 2x106/kg CD34
positive cells were applied. Stem cells were thawed at bedside and infused via central
venous catheter.
Concomitant treatments were conducted according to local standards, e.g. for antiemetic
prophylaxis, hydration and parenteral nutrition. At the time of trial initiation, a
prophylactic antibiotic treatment was recommended due to local standards, e.g.
ciprofloxacin. For PJP prophylaxis co-trimoxazole was mandatory until recovery to a CD4-cell
count of 200/µl had been reached or until day 100 post stem cell re-transfusion. In cases of
symptomatic CMV-reactivation, treatment with ganciclovir was recommended. In addition,
maintenance of immunoglobulin levels at concentrations >5g/l was recommended. G-CSF support
was optional after salvage or high dose therapy (5µg/kgbw).
Diagnostic evaluation: Throughout the entire treatment, routine laboratory investigations
were performed. In addition, CMV-reactivation screening was mandatory in CMV positive
patients. staging procedures including CT-scans were scheduled at baseline, prior to HDT and
2, 6, 9, 12, 18, 24, 36 months after HDT, and thereafter as clinically indicated. Responses
were assessed using the criteria of Cheson et al. BM was evaluated at baseline, and
re-evaluation was only needed to confirm complete remission.
Statistical analysis The primary efficacy endpoint of the study was progression-free
survival (PFS), as calculated for the intent-to-treat population. Event-free survival was
defined as the time from the date of trial inclusion to the time of either disease
progression or death (irrespective of cause) or the latest follow-up without progression.
Secondary efficacy endpoints were overall response rate at day 60 post stem cell
re-transfusion, overall survival (time from inclusion to death, irrespective of cause),
safety and side effects, toxicity of high dose therapy according to Bearman score, and
number of CMV-reactivations. Further endpoints, which will be reported separately, were the
percentage of patients being negative for minimal residual disease (MRD) by either t(14;18)
- FL or t(11;14) - MCL PCR, time to immune reconstitution with achievement of a CD4 count of
200/µl.
Results for time-to-event endpoints were analysed according to Kaplan-Meier estimator, and
comparisons were performed with the log-rank test. P <0.05 was considered statistically
significant. GraphPad Prism version 5.0 for Windows, (GraphPad Software, CA, USA) was used
for all calculations. Statistical advice was given by the Institute of Epidemiology and
Biometrical Statistics at the University of Mainz.
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Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment