Publication Only: Aggressive non-Hodgkin lymphoma - Clinical
Burkitt leukemia and lymphoma can be cured in majority of patients with intensified immune chemotherapy protocols. For patients who replapse or are even refractory (r/r) the prognosis is dismal. Blinatumomab (Blin) is a CD19 targeted bispecifc T-cell engager, which induces as a single agent complete remissions in patients with r/r B-precursor ALL at a target dose of 28 mg/d. For NHL, the target dose of Blin is 112 mg/d, which is reach after 2 weeks for therapy. Nevertheless, despite the slow ramp of the target does grade III/IV neurotoxicity (NT) is observed in 25% of patients.
In this report we tested if Blin has therapeutic activity in r/r Burkitt lymphoma/leukemia patients treated on named access base. In addition we evaulated, whether the p-selectin inhibitor pentosan polysulfate sodium (PPS), can reduced the rate of severe neurotoxicity and allows a fast ramp to meet the effective target dose of 112 mg/d Blin after 96 hours for this highly aggressive disease.
Patients with r/r Burkitt Lymphoma, refractory to first salvage chemotherapy (age 22-31) were treated with Blin continous infusion for 4 days (d) with 28 mg/d, then 52 days with 112 mg/d. Responders were offered for two weeks (w) later two cycles 28d Blin consolidation with a 4w break between. Maintanance was initiated 6w later four times (28d on, 8 weeks off). Blin was applied at 28 mg/d for 4 days and 112 mg/d for 24 days respectively. Response was document by PET-CT scans, bone marrow assessment including MRD testing by IG PCR. Safety was graded by CTCAE 4.0, CRS by Lee criteria. For preventing NT, PPS was given orally for the first 7 days together with Levetiracetam.
All three patients, who were initially treated with the GMALL 2003 protocol, had received as last salvage therapy R-ICE or R-DHAP, to which they were refractory. One patient reached a CR on day 56 whereas the other two patients had progressive disease on day 28 and died shortly after despite several treatment attemps. The responding patient developed grade II CRS and pseudoprogression whereas the two nonresponders only showed grade I CRS. The target dose of 112md was reached in all three patients with only transient grade 1 NT in one patient.
The responder opted to proceed to 12 GyTBI + 2000 mg/m2 Cy for 3 days and an autologous HSCT transplantion followed by bulk irradition. The patient relapsed one month later with Burkitt leukemia but no nodal reoccurence. Retreatment with Blin with the described schedule was initiated resulting in a second Blin induced CR with a complete MRD response on day 28. The patient then received 2 cycles of consolidation and 4 cycles of maintenance Blin and is now 18 months in continous CR with complete MRD resonse. During the induction period grade II CRS, requiring Toczilizumab, and transient grade III NT was documented. Treatment was not interrupted. Overall 10 cycles of Blina were initiated and only one brief short NT grade III was documented despite the fast ramp up to the 112 mg/d target dose under the NT protection with PPS.
Blin can be applied safely with PPS despite a fast dose escalation schedule and shows activiy in r/r Burkitt Leukemia and Lymphoma. Blin will be further evaluated in a phase II trial within the GMALL study group.