Phase I Trial of Recombinant Immunotoxin Anti-Tac(Fv)-PE38 (LMB-2) in Patients With Hematologic Malignancies

PURPOSE: To evaluate the toxicity, pharmacokinetics, immunogenicity, and antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin.PATIENTS AND METHODS: Patients with CD25+hematologic malignancies for whom standard and salvage therapies failed were treated with LMB-2 at dose levels that ranged from 2 to 63 μg/kg administered intravenously over 30 minutes on alternate days for three doses (QOD × 3).RESULTS: LMB-2 was administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at the 63 μg/kg level was reversible and included transaminase elevations in one patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in nine patients at the maximum-tolerated dose (40 μg/kg QOD × 3); toxicity was transient and most commonly included transaminase elevations (eight patients) and fever (seven patients). Only six of 35 patients developed significant neutralizing antibodies after the first cycle. The median half-life was 4 hours. One hairy cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin’s disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2 to 5 log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly. All four patients with HCL responded to treatment.CONCLUSION: LMB-2 has clinical activity in CD25+hematologic malignancies and is relatively nonimmunogenic. It is the first recombinant immunotoxin to induce major responses in cancer. LMB-2 and similar agents that target other cancer antigens merit further clinical development.

Download Full-text

Regression of Adult T-Cell Leukemia with Anti-CD25 Recombinant Immunotoxin LMB-2 Preceded by Chemotherapy

Blood ◽

10.1182/blood.v118.21.2575.2575 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2575-2575 ◽

Cited By ~ 2

Author(s):

Robert J. Kreitman ◽

Rajat Singh ◽

Maryalice Stetler-Stevenson ◽

Thomas A. Waldmann ◽

Ira Pastan

Keyword(s):

T Cell ◽

B Cells ◽

Complete Resolution ◽

Neutralizing Antibodies ◽

Bone Marrow Involvement ◽

Severe Thrombocytopenia ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Recombinant Immunotoxin

Abstract Abstract 2575 Background: Adult T-cell leukemia (ATL) is a highly aggressive CD25+ HTLV-1-associated malignancy with median survivals of 4 and 9 months for leukemic and lymphomatous forms, respectively. There is no standard therapy capable of altering median survival by more than a few months. The anti-CD25 recombinant immunotoxin LMB-2 as a single agent was previously reported in phase I testing to have activity, but limited by rapid tumor growth between cycles and immunogenicity. Human CD25+ xenografts in mice contained soluble CD25 (sCD25) levels >100-fold higher than in serum, which were rapidly depleted by chemotherapy. Treatment with fludarabine was previously reported to be associated with lower immunogenicity to murine antibodies (HAMA), and the fludarabine-cyclophosphamide (FC) combination was reported associated with reductions in normal T- and B-cells. Methods: To prevent the formation of neutralizing antibodies and enhance anti-tumor activity, leukemic or lymphomatous ATL patients received FC chemotherapy with fludarabine 25 mg/m2 and cyclophosphamide 250 mg/m2 on days 1, 2, and 3, and 2 weeks later began cycles every 3 weeks in which FC was administered on days 1, 2 and 3, followed by LMB-2 30–40 ug/Kg on days 3, 5 and 7. Formation of neutralizing antibodies and clinical response were determined with each cycle. Results: Interim results with 8 evaluable patients receiving 28 cycles (2–5 each) include an ORR of 50% with 2 CRs and 2 PRs. In 6 patients with circulating ATL cells detectable in the blood, reductions of ATL cells varied from 90.8 to 100% compared to baseline. CRs were associated with complete resolution of chest wall and pelvic masses, circulating ATL cells, and bone marrow involvement as assessed by immunohistochemistry and flow cytometry. One of 2 PRs is ongoing for nearly 1 year after complete resolution of skin involvement and partial decrease in circulating ATL cells. One of 2 CRs recurred after 6 months only in a sanctuary site (testis). The toxicity of LMB-2 was not increased by FC and 40 ug/Kg of LMB-2 days 3, 5 and 7 was not associated with dose-limiting toxicity (DLT). While the original doses of FC used were also without DLT, escalation to 30 and 300 mg/m2/day x3 resulted in severe thrombocytopenia in 1 of 2 patients. The most common toxicities, based on percent of cycles observed, were neutropenia (69%), lymphopenia (52%), leukopenia and nausea (48%), and anemia, thrombocytopenia and fever (41%). With FC, normal T-cells were reduced 0–95% (median 70%), but normal B-cells were reduced 91–100% (median 96%). Two (25%) patients made high levels of neutralizing antibodies after 3–4 cycles of LMB-2. Conclusions: LMB-2 is effective in ATL when preceded by FC, and can achieve major responses including CR. Additional patients will be needed to determine if FC can delay immunogenicity significantly, and allow enough cycles to result in long-term remission from this disease (Supported in part by NCI, intramural research program, NIH). Disclosures: Kreitman: NIH: Patents & Royalties. Off Label Use: Use of investigational agent and FC chemotherapy for treatment of ATL. Pastan:NIH: Patents & Royalties.

Download Full-text

Scabies superimposed on skin lesions of adult T-cell leukemia/lymphoma: case report and literature review

International Journal of Dermatology ◽

10.1111/j.1365-4632.2008.03707.x ◽

2008 ◽

Vol 47 (11) ◽

pp. 1168-1171 ◽

Cited By ~ 5

Author(s):

Rieko Kabashima ◽

Kenji Kabashima ◽

Ryosuke Hino ◽

Takatoshi Shimauchi ◽

Yoshiki Tokura

Keyword(s):

Case Report ◽

T Cell ◽

Literature Review ◽

Skin Lesions ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia

Download Full-text

Adult T-cell leukemia/lymphoma: report of two cases

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86822008000300012 ◽

2008 ◽

Vol 41 (3) ◽

pp. 288-292 ◽

Cited By ~ 4

Author(s):

Ricardo Aparecido Olivo ◽

Fabrício Frederico Mendes Martins ◽

Sheila Soares ◽

Helio Moraes-Souza

Keyword(s):

T Cell ◽

Clinical Laboratory ◽

Skin Lesions ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Laboratory Findings ◽

Adult T Cell Leukemia ◽

Human T Cell ◽

Disease Case

Adult T-cell leukemia/lymphoma is a lymphoproliferative disorder of mature T lymphocytes associated with infection with human T-cell lymphotrophic virus type I (HTLV-I). Adult T-cell leukemia/lymphoma is characterized by clinical and laboratory polymorphism that allows it to be classified into four distinct subgroups: smoldering, chronic, acute and lymphomatous types. We present here two cases of adult T-cell leukemia/lymphoma, respectively in the acute and lymphomatous forms of the disease. Case 1 was a 35-year-old woman who presented abdominal distension accompanied by hepatosplenomegaly, adenomegaly, skin lesions, positivity for anti-HTLV-I antibodies and leukocytosis with the presence of flower cells. Case 2 was a 38-year-old man who was admitted with generalized lymphadenomegaly, positivity for anti-HTLV-I antibodies, hypercalcemia and osteolytic lesions. In this paper, we correlate the clinical-laboratory findings of these two cases with data in the literature.

Download Full-text

Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

Blood ◽

10.1182/blood-2011-08-374561 ◽

2012 ◽

Vol 119 (1) ◽

pp. 180-187 ◽

Cited By ~ 29

Author(s):

Eugenio Gaudio ◽

Riccardo Spizzo ◽

Francesco Paduano ◽

Zhenghua Luo ◽

Alexey Efanov ◽

...

Keyword(s):

T Cell ◽

Hematologic Malignancies ◽

Lymphocytic Leukemia ◽

Chromosomal Translocations ◽

Human Leukemia ◽

Cell Leukemia ◽

Ataxia Telangiectasia Mutated ◽

Interacting Protein ◽

Aggressive Form ◽

Subsequent Activation

Abstract The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.

Download Full-text

Effect of a novel anti-CCR4 monoclonal antibody (Mogamulizmab) on skin lesions of adult T-cell leukemia-lymphoma (ATL) and its adverse skin reactions (ASR)

Retrovirology ◽

10.1186/1742-4690-11-s1-p24 ◽

2014 ◽

Vol 11 (S1) ◽

Cited By ~ 1

Author(s):

Kentaro Yonekura ◽

Tamotsu Kanzaki ◽

Nobuaki Nakano ◽

Masahito Tokunaga ◽

Ayumu Kubota ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Skin Lesions ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Skin Reactions ◽

Adult T Cell Leukemia

Download Full-text

A proposal for smoldering adult T-cell leukemia: a clinicopathologic study of five cases

Blood ◽

10.1182/blood.v62.4.758.bloodjournal624758 ◽

1983 ◽

Vol 62 (4) ◽

pp. 758-766 ◽

Cited By ~ 4

Author(s):

K Yamaguchi ◽

H Nishimura ◽

H Kohrogi ◽

M Jono ◽

Y Miyamoto ◽

...

Keyword(s):

T Cell ◽

Skin Lesions ◽

Serum Lactate ◽

Serum Lactate Dehydrogenase ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Normal Range ◽

Adult T Cell Leukemia ◽

Clinicopathologic Study ◽

Cryptococcus Meningitis

We have observed five patients with smoldering adult T-cell leukemia (ATL) who had skin lesions as premonitory symptoms. The illness developed slowly, but flared up after several years. Skin lesions appeared in the form of erythema, papules, or nodules. Infiltration of the skin by ATL cells was slight, and the proportion of ATL cells in the peripheral blood was 0%-2%. The serum lactate dehydrogenase (LDH) value was within normal range and was not associated with hypercalcemia; lymphadenopathy, hepatosplenomegaly, and bone marrow infiltration were very slight. In most cases, hypergammaglobulinemia was seen, and in one case, monoclonal hypergammaglobulinemia was observed. All five patients had lived in an area in which ATL was endemic, and their anti-ATLA antibodies were positive; none had ever received a blood transfusion. One patient developed typical ATL after more than 13 yr of illness and died of renal insufficiency. Another patient developed typical ATL after 5 yr of illness and died of cryptococcus meningitis. Based on clinical and pathologic differences, we believe that these cases should be distinguished from typical ATL cases for the purposes of prognosis and treatment.

Download Full-text

Clinical characteristics of adult T-cell leukemia/lymphoma infiltration in the gastrointestinal tract

10.21203/rs.2.24209/v2 ◽

2020 ◽

Author(s):

Tadashi Miike ◽

Hiroshi Kawakami ◽

Takuro Kameda ◽

Shojiro Yamamoto ◽

Yoshihiro Tahara ◽

...

Keyword(s):

T Cell ◽

Clinical Characteristics ◽

Skin Lesions ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Gi Tract ◽

Cell Leukemia Virus Type ◽

Gi Endoscopy ◽

Adult T Cell Leukemia ◽

Fold Type

Abstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1. The clinical course of ATLL is very heterogeneous, and many organs, including the gastrointestinal (GI) tract, can be involved. However, there are few detailed reports on ATLL infiltration in the GI tract. We investigated the clinical characteristics of ATLL infiltration in the GI tract.Methods: This retrospective observational single-center study included 40 consecutive ATLL patients who underwent GI endoscopy. The patients’ demographic and clinical characteristics and endoscopic findings were analyzed retrospectively. Patients with ATLL who were diagnosed by histological examination were divided into two groups based on GI tract infiltration.Results: Multivariate analysis revealed that the absence of skin lesions was significantly associated with GI infiltration (P < 0.05). Furthermore, the infiltration group tended to have similar macroscopic lesions in the upper and lower GI tracts, such as diffuse type, tumor-forming type, and giant-fold type.Conclusions: GI endoscopy may be considered for ATLL patients without skin lesions.

Download Full-text

Clinical characteristics of adult T-cell leukemia/lymphoma infiltration in the gastrointestinal tract

10.21203/rs.2.24209/v1 ◽

2020 ◽

Author(s):

Tadashi Miike ◽

Hiroshi Kawakami ◽

Takuro Kameda ◽

Shojiro Yamamoto ◽

Yoshihiro Tahara ◽

...

Keyword(s):

T Cell ◽

Clinical Characteristics ◽

Skin Lesions ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Gi Tract ◽

Adult T Cell Leukemia ◽

Endoscopic Findings ◽

Human T Cell ◽

Single Center Study

Abstract Background: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell lymphotropic virus type 1 (HTLV-1). The clinical course of ATLL is very heterogeneous, and many organs, including the gastrointestinal (GI) tract, can be involved. However, there are few detailed reports on ATLL infiltration in the GI tract. We investigated the clinical characteristics of ATLL infiltration in the GI tract.Methods: This retrospective observational single center study included 40 consecutive ATLL patients who underwent GI endoscopy. The patients’ demographic and clinical characteristics and endoscopic findings were analyzed retrospectively. Patients with ATLL who were diagnosed via histological examination, were divided into two groups based on GI tract infiltration.Results: Multivariate analysis revealed that the absence of skin lesions was significantly associated with GI infiltration (P < 0.05). Furthermore, the infiltration group tended to have similar macroscopic lesions in the upper and lower GI tracts.Conclusions: The absence of skin lesions and characteristic endoscopic findings may aid in detecting ATLL infiltration in the GI tract.

Download Full-text