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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
About 80% of patients with HCL can achieve long-term remissions following treatment with purine analogs, such as cladribine and pentostatin, with/without rituximab, and an OS approaching that of the general population. Responses, however, are not always durable; about 30% of the patients relapse, and subsequent responses are poor. At progression, therapies include the recently approved anti-CD22 immunotoxin, moxetumomab pasudotox, following at least two prior therapies, and the BRAF inhibitor, vemurafenib, which is being tested as monotherapy or combined with MEK inhibitors.174
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
A principal challenge in the treatment is the presence of infections which impacts the use of the purine analogues, in view of the associated myelosuppression. Following pre-clinical studies suggesting functionality of BRAF in HCLc, two phase II studies with a BRAF inhibitor, vemurafeneb, were completed in 2016. These observed responses were in 39% of patients with HCL refractory to purine therapy. Side effects were principally cutaneous, involving rash but interestingly, and rather worrisome, was the occurrence of low-grade cutaneous tumours; arthralgia and arthritis were also noted. Resistance to the BRAF inhibitor was, however, frequent, with the emergence of ERK-positive leukaemic cells, suggesting bypass reactivation of MEK and ERK as a resistance mechanism. In efforts to circumvent vemurafenib resistance, the combination of BRAF and MEK inhibitors, which oppose ERK-rephosphorylating mechanisms, and combining BRAF inhibitors with rituximab, are being tested. Vemurafenib is also being tested as a potential first-line treatment for patients who cannot receive purine analogues due to ongoing infections. Other investigational approaches of interest include the BTK inhibitor, ibrutinib, and an anti-CD22 immunotoxin conjugate, moxetumomab pasudotox (CAT08015). A phase I study of moxetumomab demonstrated remarkable activity, with 46% of patients with relapse/refractory disease achieving CR; a confirmatory single arm phase III study is in progress. The preliminary results are encouraging and in April 2018, the drug was granted a priority review by the US Food and Drug Administration.
Spleen
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
HCL-V (CD103+/CD25− HCL) is a rare B-cell disorder that accounts for ~10% of HCL cases and presents with splenomegaly, lymphocytosis, and cytopenias without monocytopenia. HCL-V includes cases of B-cell chronic lymphoproliferative disorders that resemble classic HCL but exhibit variant clinical features (such as leukocytosis, presence of monocytes, cells with prominent nucleoli, cells with blastic or convoluted nuclei, and/or absence of irregular cytoplasmic borders), variant immunophenotype [i.e., absence of CD25 expression, annexin-A1, or tartrate-resistant acid phosphatase (TRAP)] and resistance to conventional HCL therapy (i.e., lack of response to cladribine) [21]. HCL-V is not biologically related to HCL. HCL-V frequently involves the spleen, BM, and blood. Middle-aged to elderly patients are affected with slight male predominance. Patients have indolent course with a long survival time. Treatment with Rituxan and anti-CD22 immunotoxin is highly effective. It shares more similarities with SMZL (splenic lymphoma with villous lymphocytes) and SDRPL than with HCL [52]. HCL-V differs from typical HCL by worse prognosis and poor response to interferon alpha and purine analogs, cladribine or pentostatin. New agents, such as rituximab and BL22 (anti-CD22 immunotoxin), are actively being evaluated and show promising results in both classical HCL and CD25− variant.
Treatment of hairy cell leukemia
Published in Expert Review of Hematology, 2020
Dai Chihara, Robert J. Kreitman
Recombinant immunotoxins are chimeric proteins containing a fragment of a monoclonal antibody connected to a protein toxin in a manner which does not require chemical conjugation [47]. Bacterial toxins like Pseudomonas exotoxin A (PE) and diphtheria toxin (DT) are optimal for creating chimeric recombinant toxins, since these bacterial toxins are naturally made as single chains [48]. The recombinant anti-CD22 immunotoxin BL22 was developed containing PE38, a 38 kDa truncated form of Pseudomonas exotoxin [49–52]. BL22 was tested in phase 1 and 2 clinical trials, achieving CR rates of 47–61% in patients with HCL [34,53,54]. In targeting CD22 with PE38, a reversible form of hematolytic uremic syndrome (HUS) was observed in 5–12% of patients. Unlike HUS due to Shiga-like toxin, HUS due to BL22 did not require plasmapheresis for complete resolution and did not recur.
Moxetumomab pasudotox for the treatment of relapsed and/or refractory hairy cell leukemia
Published in Expert Review of Hematology, 2019
Iman Abou Dalle, Farhad Ravandi
HCL is one of the B-cell malignancies expressing high levels of CD22 surface antigens at a median of ~40.000 CD22 sites/cell, ranging from 10.000 until >100.000/cell, unlike chronic lymphocytic leukemia (CLL) and acute B-lymphoblastic leukemia (B-ALL) which express 1200 to 4500 CD22 sites/cell [28]. The high level of CD22 expression on HCL cells provided the rationale for the development of an immunotoxin directed against CD22 antigens [29,30]. The first generation of the recombinant anti-CD22 immunotoxin, BL-22 for ‘B-cell Leukemia’ (also named CAT-3888) was investigated in phase I and II trials in R/R HCL. CR rates were achieved in 47% to 61% of treated patients. A unique serious adverse event was reversible hemolytic uremic syndrome (HUS) seen in eight (12%) patients [31–33]. BL-22 was very promising in R/R HCL, however, its activity was much lower in CLL, and B-ALL, likely because of the differential expression of CD22 surface antigens between different diseases [32,34].
Diagnostic and therapeutic challenges in hairy cell leukemia-variant: where are we in 2021?
Published in Expert Review of Hematology, 2021
The anti-CD22 immunotoxin BL22 contains an Fv fragment fused to a truncated pseudomonas exotoxin. This agent has shown activity in purine analog refractory typical HCL. The first results showed a CR achievement in three HCL-V treated with this agent. However, the responses were short lived, less than 12 month duration in two patients. Still, these patients achieved a second CR when received the agent for the second time [48].