Table 3.

Published clinical studies of proteasome inhibitors in leukemia

Study drugs	Cohort	Number	Phase	Study results and mechanisms involved	Refs.
BTZ	Several hematologic malignancies	27	I	Bortezomib was given twice weekly for 4 weeks every 6 weeks. The MTD was 1.04 mg/m2. CR in 1 MM patient. PR in 1 patient with MCL and 1 with FL.	[128]
BTZ	Refractory or relapsed acute leukemia	15	I	Bortezomib was given twice weekly for 4 weeks every 6 weeks. The MTD was 1.25 mg/m2. No ≥grade 3 toxicities. 5 patients showed hematological improvement. No CR achieved.	[129]
BTZ, PegLD	AML, MM, and NHL	42	I	Bortezomib was given on days 1, 4, 8, and 11 and PedLD on day 4. MTD of BTZ 1.3 mg/m2. No significant pharmacokinetic and pharmacodynamic interactions between bortezomib and PegLD. 16 of 22 MM patients achieved CR, near-CR or PR. 1 CR and 1 PR in NHL patients. 2 of 2 AML patients achieved a PR.	[130]
BTZ	Recurrent childhood ALL, AML, blastic phase CML, M3	12	I	Bortezomib was administered twice weekly for 2 weeks followed by a 1-week rest. MTD of bortezomib was 1.3 mg/m2/dose. 5 patients were fully evaluable. DLT’s occurred in 2 patients at the 1.7 mg/m2 dose level. No OR achieved.	[131]
BTZ, IDA, AraC	AML	31	I	Addition of BTZ to AML induction chemotherapy. Bortezomib added on days 1, 4, 8, and 11. 19 CR, 3 CRp, 2 PR and 7 no response. BTZ was well-tolerated up to 1.5 mg/m2.	[132]
BTZ, VCR, DEX, PegAspa, DOX	Recurrent childhood ALL	10	I	Combination of bortezomib (1.3 mg/m2) with ALL induction therapy is active with acceptable toxicity. 6 patients achieved CR.	[133]
BTZ, VCR, DEX, PegAspa, DOX	Recurrent childhood ALL	22	II	14 patients achieved CR, and 2 achieved CRp, 3 patients died from bacterial infections, 2 of 2 included T cell ALL patients did not respond.	[134]
BTZ, tipifarnib	Relapsed or refractory ALL(26) or AML (1)	27	I	Combination well tolerated. 2 patients achieved CRp and 5 SD.	[135]
BTZ, DNR, AraC	AML (age > 65)	95	I/II	Combination was tolerated. 62 patients achieved CR and 4 patients CRp.	[136]
BTZ, 17-AAG	Relapsed or refractory AML	11	I	The combination of 17-AAG and BTZ led to toxicity without measurable response in patients with relapsed or refractory AML.	[137]
BTZ, DAC	Poor-risk AML	19	I	Combination was tolerable and active in this cohort of AML patients; 7 of 19 patients had CR or CRi. 5 of 10 patients > 65 years had CR.	[138]
BTZ, LEN	14 MDS/CMML 9 AML	23	I	MTD of BTZ 1.3 mg/m2 was tolerable in this regimen. Responses were seen in patients with MDS and AML. Two fatal infections occurred.	[139]
BTZ, IDA	Relapsed AML (7) or AML > 60 years (13)	20	I	4 patients achieved complete remission. 1 treatment-related death. Overall the combination was well tolerated.	[140]
BTZ, AZA	Relapsed or refractory AML	23	I	Dose of 1.3 mg/m2 BTZ was reached without dose-limiting toxicities. 5 out of 23 patients achieved CR.	[141]
BTZ, MIDO vs BTZ, MIDO, DHAD, etoposide, AraC	Relapsed/refractory AML	21	I	56.5% CR rate and 82.5% overall response rate (CR + CR with incomplete neutrophil or platelet count recovery). Combination is active but is associated with expected drug-related toxicities. DLTs were peripheral neuropathy, decrease in ejection fraction and diarrhea.	[142]
CFZ + dexamethasone	Refractory or relapsed acute leukemia	18	I	CFZ was given twice weekly for 4 weeks with a maximal of 6 cycles. Prior to CFZ dexamethasone was given. The MTD was not established, because no DLTs were observed (36–46 mg/m2). PR in 2/10 patients and 4/10 SD.	[143]
CFZ + dexamethasone	Previously treated patient with CLL or SLL	19	I	CFZ was given twice weekly for 3 weeks in a 28-day cycle. Prior to CFZ dexamethasone was given. No DLTs observed and all available patients for evaluation had SD (including patients with Del(17p13.1) and fludarabine-resistant disease.	[144]
BTZ, cytarabine, idarubicin vs BTZ, cytarabine etoposide	Children with relapsed, refractory, or secondary AML	37	II	BTZ, 1 or 1.3 mg/m2, was given at days 1, 4, and 8 in combination with idarubicin and cytarabine (arm A) or with etoposide and high dose cytarabine (arm B). Hypokalemia incidence was high, 17%. Four deaths occur, 3 infectious deaths and one from PD. Both arms failed to meet predetermined efficacy thresholds (CRi was not included). Arm A: CR = 21.4%, CRp + CRi = 35.6%, PR = 14.3%. Arm B: CR = 34.8%, CRp + CRi = 13% and one death.	[145]
BTZ	Relapsed/refractory ATL	15	II	BTZ, 1.3 mg/m2, was given at days 1, 4, 8, and 11. After stage 1, all patients discontinued treatment (PD = 11, AEs = 3) and the study was terminated because BTZ was not considered promising enough as a single agent. 12 patients had Gr 3/4 drug-related AEs of which 2 Gr3/4 peripheral neuropathy. Overall responses: PR = 1, SD = 5. ORR = 6.7%, PFS = 38 days (8–122).	[146]
BTZ, DEX, DOX vs BTZ, DEX, cyclophosphamide	Newly diagnosed primary plasma cell leukemia	39	II	Four alternating cycles of BTZ (1.3 mg/m2 on days 1, 4, 8, and 11), DEX plus DOX, or cyclophosphamide was given. 35 patients completed the 4 cycles. ORR = 69%, CR = 10%, VGPR = 26%, PR = 23%. 10 were refractory to the induction phase, and 2 deaths due to sepsis occur. 25 patients underwent HDM/ASCT and 1 a syngeneic allograft. After ASCT: ORR = 92% CR = 34%, VGPR = 38%, PR = 16%, PD = 8%. In the intention-to-treat population, the median PFS = 15.1 months and overall survival = 36.3 months.	[147]

Updated from Franke et al. [67]

Abbreviations: Study outcome: MTD maximum tolerated dose, DLT dose-limiting toxicities, CR complete response, CRi incomplete remission, CRp CR with incomplete platelet recovery, PR partial response, OR objective response, SD stable disease, PFS progression-free survival, EFS event-free survival, OS overall survival. Malignancies: MCL mantle cell lymphoma, FL follicular lymphoma, NHL non-Hodgkin lymphoma. Drugs: 17-AAG 17-N-Allylamino-17-Demethoxygeldanamycin, AraC cytarabine, AZA azacitidine, BTZ bortezomib, CFZ carfilzomib, DAC decitabine, DEX dexamethasone, DHAD mitoxantrone, DNR daunorubicin, DOX doxorubicin, IDA idarubicin, LEN lenalidomide, PegLD pegylated liposomal doxorubicin, PegAspa pegylated L-asparaginase, VCR vincristine