Successful treatment and re-treatment of resistant B-cell chronic lymphocytic leukemia with the monoclonal anti-CD 20 antibody rituximab

Herold, Michael; Schulze, Arik Bernard; Hartwig, Kerstin; Anger, G

doi:10.1007/s002779900141

Cited by 15 publications

(5 citation statements)

References 10 publications

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“…Fludarabine is also an effective agent when used as second-line therapy 11,12 and is more effective in this setting than combination chemotherapy such as CAP (cyclophosphamide, Adriamycin [doxorubicin], prednisolone). 7 Recently there has been considerable interest in antibody-based approaches [13][14][15][16][17][18][19] both alone and in combination. These can result in excellent responses in some patients, with a proportion becoming negative for molecular markers for CLL.…”

Section: Introductionmentioning

confidence: 99%

Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses

Milligan

Fernandes

Dasgupta

et al. 2005

Blood

103

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We have assessed autologous stem cell transplantation after treatment with fludarabine in previously untreated patients with chronic lymphocytic leukemia (CLL). This study is the first to enroll previously untreated patients and follow them prospectively. The initial response rate to fludarabine was 82% (94 of 115 patients). Stem cell mobilization was attempted in 88 patients and was successful in 59 (67%). Overall 65 of 115 patients (56%) entered into the study proceeded to autologous transplantation. The early transplant-related mortality rate was 1.5% (1 of 65 patients). The number of patients in complete remission after transplantation increased from 37% (24 of 65) to 74% (48 of 65), and 26 of 41 patients (63%) who were not in complete remission at the time of their transplantation achieved a complete remission after transplantation. The 5-year overall and disease-free survival rates from transplantation were 77.5% (CI, 57.2%-97.8%) and 51.5% (CI, 33.2%-69.8%), respectively. None of the variables examined at study entry were found to be predictors of either overall or disease-free survival. Sixteen of 20 evaluable patients achieved a molecular remission on a polymerase chain reaction (PCR) for immunoglobulin heavy-chain gene rearrangements in the first 6 months following transplantation. Detectable molecular disease by PCR was highly predictive of disease recurrence. IntroductionChronic lymphocytic leukemia (CLL) is characterized by the gradual accumulation of small mature B lymphocytes in the blood, bone marrow, and lymphoid organs. Alkylating agents such as chlorambucil, either alone or with steroids, have traditionally been the mainstay of treatment for patients with advanced stage disease, 1 but do not appear to improve overall survival. Combination chemotherapy, 1-5 particularly with the addition of an anthracycline, 3,6,7 has also been effective at palliating disease. More recently the nucleoside analogues, in particular fludarabine, have induced good responses both in previously untreated patients 7-9 and in patients who are refractory to standard therapy. [10][11][12] When fludarabine is used to treat previously untreated patients, it is demonstrably better than chlorambucil, 9 and at least as effective as CHOP 7 (cyclophosphamide, hydroxydaunorubicin, Oncovin [vincristine], prednisone) in terms of responses obtained. Evidence indicates that the duration of remissions induced by fludarabine in previously untreated patients is longer, 9,12 although this has not yet been shown to translate into a benefit in overall survival. Fludarabine is also an effective agent when used as second-line therapy 11,12 and is more effective in this setting than combination chemotherapy such as CAP (cyclophosphamide, Adriamycin [doxorubicin], prednisolone). 7 Recently there has been considerable interest in antibody-based approaches [13][14][15][16][17][18][19] both alone and in combination. These can result in excellent responses in some patients, with a proportion becoming negative for molecular markers for CLL. 20 A ...

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Section: Introductionmentioning

confidence: 99%

Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses

Milligan

Fernandes

Dasgupta

et al. 2005

Blood

103

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“…The adverse events were fever, chills, rigors, hypotension and bronchospasm. Premedication with prednisone (100 mg) 30 min prior to the infusion of rituximab may prevent cytokine release and improves tolerance of the antibody infusion [41]. In patients with CLL who received premedication consisting of antipyretic and antihistamine drugs together with corticosteroids, infusion-related side-effects were usually only mild or moderate and did not require discontinuation of rituximab administration [42].…”

Section: Rituximabmentioning

confidence: 98%

Novel Monoclonal Antibodies for the Treatment of Chronic Lymphocytic Leukemia

Robak

2008

CCDT

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For many years, alkylating agents and purine nucleoside analogs (PNA) have been considered the drug of choice for treatment of chronic lymphocytic leukemia (CLL). More recently the introduction of monoclonal antibodies (mAb), especially rituximab directed against CD20 and alemtuzumab directed against CD52, has renewed interest in CLL therapy. Over the last few years, several new mAbs directed against lymphoid cells have been developed and investigated in preclinical studies and clinical trials. Some of them are highly active in CLL. New mAbs directed against CD20 include human mAb ofatumumab (HuMax CD20), IMMU-106 (hA20) which has a >90% humanized framework and GA-101, a novel third - generation fully humanized and optimized mAb. These agents are highly cytotoxic against B-cell lymphoid cells and are evaluated in CLL. Lumiliximab (anti-CD23 mAb) is a genetically engineered macaque-human immunoglobulin (Ig) A1. This antibody showed high activity and good tolerability in phase I clinical trial and is evaluated in phase I/II clinical trials as a single agent and in combination. Epratuzumab is a humanized anti-CD22 mAb currently used in clinical trials for treatment of non-Hodgkin lymphoma and autoimmune disorders. Further studies are needed to elucidate the role of this agent in CLL. Apolizumab (HU1D10) is a humanized IgG1 antibody specific for a polymorphic determinant found on the HLA-DRbeta chain. Preclinical and early clinical studies suggest that this mAb has some activity in CLL. HCD122 (CHIR-12.12) and SGN-40 are anti-CD40 mAbs which induce cytotoxicity against CLL cells. Phase I study has shown a favorable safety profile and some activity of HCD122 in pretreated CLL patients. Immunotoxins, especially BL22, LMP-2 and denileukin diftitox, are also being evaluated in lymphoid malignancies and seem to be active in CLL. Finally, antiangiogenic mAbs, especially bevacimzumab, have a potential therapeutic role in this disease. In this review, new mAbs, potentially useful in CLL are presented.

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“…These patients should be observed for tumor lysis and hypoxemia. Premedication with prednisone (100 mg) 30 min prior to the infusion of RIT may prevent cytokine release and improved tolerance of the antibody infusion [56]. In patients with B-CLL who received premedication consisting of antipyretic and antihistaminic drugs together with corticosteroids infusion-related side-effects were usually only mild or moderate and did not require discontinuation of RIT administration [57].…”

Section: Rituximabmentioning

confidence: 98%

Monoclonal Antibodies in the Treatment of Chronic Lymphoid Leukemias

Robak

2004

Leukemia & Lymphoma

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In recent years preclinical and clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) either alone or coniugated to toxins in patients with several lymphoid malignancies, including chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL). Two MoAbs, directed against CD20 antigen (Rituximab, RIT) and CD52 antigen (Campath-1H, alemtuzumab, ALT) demonstrate significant activity in CLL. The most notable success to data has been achieved with ALT, both in previously treated and untreated patients with CLL. ALT is a humanized rat IgG1 antibody that binds to the cell membrane of virtually all normal as well as malignant lymphocytes. In the vast majority of CLL patients ALT causes constant reduction of abnormal blood lymphocytes, usually in less than 4 weeks, and disappearance of CD5/CD19 co-expression cells from blood. The regression of lymphoid infiltration from other sites is less clear. ALT is also highly active in patients with CLL in progression, even refractory to fludarabine (FA). Hematological toxicity, especially long-lasting lymphocytopenia, was noted in the majority of patients. The most important clinical side effects of ALT treatment were infections, mainly herpes simplex virus and cytomegalovirus reactivation. RIT is also active in CLL in conventional doses. However some studies suggest that higher doses are more effective than standard doses, used routinely in other lymphoid malignancies. The activity of ALT and RIT in CLL patients resistant to FA and their synergistic interactions with cytotoxic drugs suggests that a combination of these agents may lead to further progress in the treatment of this disease. The T-cell variant of PLL has demonstrated impressive responses to ALT in several trials even if the patients were refractory to deoxycoformycin (DCF) and other agents. However, this MoAb is not curative, because all patients eventually relapsed. Consequently, treatment with ALT may need to be associated with stem cell transplantation to consolidate and maintain long-term remissions. Recently anti-CD22 and anti-CD25 immunotoxins have been investigated in purine analogues refractory or relapsed HCL. The presented results indicate that these agents are highly active and well tolerated even if the patients were resistant to 2-CdA or DCF.

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Successful treatment and re-treatment of resistant B-cell chronic lymphocytic leukemia with the monoclonal anti-CD 20 antibody rituximab

Cited by 15 publications

References 10 publications

Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses

Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses

Novel Monoclonal Antibodies for the Treatment of Chronic Lymphocytic Leukemia

Monoclonal Antibodies in the Treatment of Chronic Lymphoid Leukemias

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