scholarly journals Targeted Alpha-Particle Immunotherapy with Bismuth-213 and Actinium-225 for Acute Myeloid Leukemia

2013 ◽  
Vol 47 (1) ◽  
pp. 14-17 ◽  
Author(s):  
Joseph G Jurcic
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Alpha Particle ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Nonspecific Cytotoxicity ◽  
Acute Myeloid ◽  
Refractory Aml

ABSTRACT Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against acute myeloid leukemia (AML). To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, lintuzumab was conjugated to the α-emitters bismuth-213 (213Bi) and actinium-225 (225Ac). The 46-minute half-life of 213Bi limits its widespread use. Therefore, 225Ac was also conjugated to various antibodies using DOTA-SCN. We conducted a phase I trial of 213Bi-lintuzumab and subsequently administered cytarabine with 213Bi-lintuzumab in a phase I/II study. The toxicity and biological activity of 225Ac-linutuzumab in patients with relapsed/refractory AML in a phase I dose-escalation trial was determined. An initial phase I trial demonstrated the feasibility, safety and antileukemic activity of 213Bi-lintuzumab. 213Bi-lintuzumab produced responses in 24% of AML patients receiving doses ≥ 37 MBq/kg after partial cytoreduction with cytarabine. 225Ac-labeled immunoconjugates killed in vitro at doses at least 1,000 times lower than 213Bi analogs. Eighteen patients with relapsed/refractory AML received 18.5 to 148 kBq/kg of 225Ac-lintuzumab in a phase I study. Dose-limiting toxicities were myelosuppression lasting >35 days in one patient and death due to sepsis in two patients. The maximum tolerated dose (MTD) was 111 KBg/kg. Bone marrow blast reductions were seen across all dose levels. Targeted α- particle immunotherapy with 213Bi- and 225Ac-lintuzumab is safe, has significant antileukemic effects, and can produce remissions after partial cytoreduction. How to cite this article Jurcic JG. Targeted Alpha-Particle Immunotherapy with Bismuth-213 and Actinium-225 for Acute Myeloid Leukemia. J Postgrad Med Edu Res 2013;47(1): 14-17.

Phase I trial of the targeted alpha-particle nano-generator actinium-225 (225Ac-lintuzumab) (anti-CD33; HuM195) in acute myeloid leukemia (AML).

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 6516-6516 ◽  
Author(s):  
J. G. Jurcic ◽  
T. L. Rosenblat ◽  
M. R. McDevitt ◽  
N. Pandit-Taskar ◽  
J. A. Carrasquillo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Alpha Particle ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Acute Myeloid

Phase I Dose Escalating Trial of Bortezomib (Velcade®) in Combination with Idarubicin and Cytarabine in Patients with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1799-1799 ◽  
Author(s):  
Eyal C. Attar ◽  
Daniel J. DeAngelo ◽  
Karen K. Ballen ◽  
Emily Learner ◽  
Elizabeth G. Trehu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Myeloid Leukemia ◽  
Science Studies ◽  
Leukemia Cell ◽  
Maximum Tolerated Dose ◽  
Synergistic Cytotoxicity ◽  
Acute Myeloid

Abstract Conventional therapy for acute myeloid leukemia (AML) consists of a combination of cytarabine and an anthracycline such as idarubicin. Currently, most patients ultimately fail treatment due to leukemia cell resistance to drug therapy. In vitro experiments have shown that the addition of a proteasome inhibitor to an anthracycline results in synergistic cytotoxicity to leukemia cells. Hence, we initiated this phase I trial in patients to see if bortezomib could be safely added to conventional treatment. Patients over age 60 with AML or any patient 18 or older with relapsed disease after a remission of at least 3 months (not refractory) were eligible. All patients received idarubicin 12 mg/m2 on days 1–3 and cytarabine 100 mg/m2 by continuous infusion days 1–7. In addition, patients received bortezomib by IV bolus on days 1, 4, 8, and 11. Cohorts of 3 to 6 patients were entered using increasing doses of bortezomib in order to determine the maximum tolerated dose (MTD). The first cohort received 0.7 mg/m2 of bortezomib with each bolus. If dose limiting toxicity (DLT) was encountered, then cohort advancement was restricted. DLTs included prolonged myelosuppression, neuropathy, and other grade 3 or 4 toxicities. Dose escalation would proceed to 1.0 mg/m2 and then to 1.3 mg/m2 if tolerated. No escalation was planned beyond 1.3 mg/m2. To date 14 patients have been entered on this study. In the first cohort of 3 patients with bortezomib at 0.7 mg/m2, a DLT due to prolonged neutropenia was encountered, so an additional 3 patients were entered at this dose level. No DLTs were encountered among these additional patients, so 3 more patients were entered with bortezomib at 1.0 mg/m2. One of these patients experienced prolonged thrombocytopenia and thus 3 additional patients were enrolled at 1.0 mg/m2. No DLTs were encountered among these additional patients, and thus the next cohort of patients with bortezomib at 1.3 mg/m2 was opened. To date, two patients have been enrolled at this dose level. The plan is to enroll a third patient at this level and to assess for possible DLTs. Among the 12 patients evaluable for response, there have been 4 patients achieving complete remission, 3 patients achieving remission without complete recovery of platelet count (CRp defined as having met criteria for CR but with 25,000–99,000 platelets/μl), 2 patients achieving a partial remission (CR but with 5–24% bone marrow blasts), and 3 patients failing to respond. In conclusion, bortezomib at 0.7 mg/m2 and 1.0 mg/m2 in the day 1, 4, 8, and 11 schedule can be added to idarubicin and cytarabine with acceptable toxicity. This study continues in an attempt to determine whether bortezomib can be escalated safely to 1.3 mg/m2 in this combination. Additional patients will be enrolled at the candidate MTD to gain confidence in the safety and activity at this level. Correlative science studies are planned.

scholarly journals Two-Stage Priming of Allogeneic Natural Killer Cells for the Treatment of Patients with Acute Myeloid Leukemia: A Phase I Trial

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0123416 ◽  
Author(s):  
Panagiotis D. Kottaridis ◽  
Janet North ◽  
Maria Tsirogianni ◽  
Chloe Marden ◽  
Edward R. Samuel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Natural Killer Cells ◽  
Phase I ◽  
Natural Killer ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Two Stage ◽  
Killer Cells ◽  
Acute Myeloid

Targeted Alpha-Particle Immunotherapy for Acute Myeloid Leukemia

2014 ◽  
pp. e126-e131 ◽  
Author(s):  
Joseph G. Jurcic ◽  
Todd L. Rosenblat
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Alpha Particle ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Myeloid Cell ◽  
Multicenter Trial ◽  
Alpha Particles ◽  
Particle Therapy ◽  
Acute Myeloid

Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 (213Bi)-labeled lintuzumab. In a subsequent study, 213Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of 213Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 (225Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that 225Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose 225Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using 213Bi- and astatine-211 (211At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.

scholarly journals Phase I trial of plerixafor combined with decitabine in newly diagnosed older patients with acute myeloid leukemia

Haematologica ◽  
2018 ◽  
Vol 103 (8) ◽  
pp. 1308-1316 ◽  
Author(s):  
Gail J. Roboz ◽  
Ellen K. Ritchie ◽  
Yulia Dault ◽  
Linda Lam ◽  
Danielle C. Marshall ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Newly Diagnosed ◽  
Acute Myeloid

Limited Phase I Trial of Sequential High Dose Cytarabine and Clofarabine (HiDAC→CLOF) in Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4565-4565
Author(s):  
Bayard L. Powell ◽  
James Lovato ◽  
Claire Kimbrough ◽  
Susan Lyerly ◽  
Sonya Galloway-Daniels ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Skin Toxicity ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

Abstract High dose cytarabine (HiDAC) is the most effective single agent for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. We conducted a two step limited phase I trial of sequential HiDAC (2g/m2 over 3 hours) followed by CLOF (30 or 40 mg/m2 infused over 2 hours), each given daily for 5 days, in adults with AML in first or second relapse or refractory to initial induction chemotherapy. Patients with persistent leukemia on day 12–14 received a second course of HiDAC→CLOF; phase I toxicity evaluation was based on cycle 1 data only. Nine patients (6 men and 3 women) were treated. The median age was 55.5 years (range 29.2 – 68.1). All had relapsed AML; two had prior autologous stem cell transplant. The initial cohort of 3 patients received clofarabine 30 mg/m2 with one dose limiting toxicity (DLT); an additional 3 patients were treated in cohort 1. The second cohort was treated with CLOF 40 mg/m2, the target dose for a planned phase II trial of HiDAC→CLOF. Hematologic toxicities and infections were not considered DLT. In the first cohort (30 mg/m2; n = 6) there was 1 DLT - grade 4 skin rash in a patient who subsequently died on day 17 with sepsis-related multi-organ failure; 3 patients had reversible grade 3 elevations in AST/ALT, 1 had grade 3 skin toxicity. In cohort 2 (40 mg/m2 ; n = 3) there was no DLT; 1 patient had grade 3 AST/ALT; 2 had grade 3 skin. Three of nine patients received a second course of induction HiDACCLOF. Two of six patients in cohort 1 achieved complete remission (CR), 1/3 patients in cohort 2 achieved CRi(CRp). Two of three CR/CRi patients received one course and one received two courses of HiDAC→CLOF induction. Conclusion: HiDAC→CLOF was associated with transient elevation in AST/ALT (4/9) and skin rash (3/9; primarily extensive palmar/plantar); skin toxicity appeared especially prominent in patients with palmar/plantar toxicity during prior therapy with HiDAC. Toxicities (other than skin) were comparable to other salvage regimens for relapsed and refractory AML. This combination is active in relapsed AML with 3/9 CR/CRp. A phase II trial of HiDAC→CLOF is underway; prophylactic intravenous hydrocortisone has been incorporated in an attempt to decrease skin toxicity.

scholarly journals Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia

2015 ◽  
Vol 106 (11) ◽  
pp. 1590-1595 ◽  
Author(s):  
Yukio Kobayashi ◽  
Takahiro Yamauchi ◽  
Hitoshi Kiyoi ◽  
Toru Sakura ◽  
Tomoko Hata ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Japanese Patients ◽  
Acute Myeloid
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