Aan dit artikel is enkele uren gewerkt. Opzoeken, vertalen, plaatsen enz. Als u ons wilt ondersteunen dan kan dat via een al of niet anonieme donatie. Elk bedrag is welkom hoe klein ook. Klik hier als u ons wilt helpen kanker-actueel online te houden
12 december 2012: ik ben kanker-actueel aan het herzien en laat deze informatie staan. Onderaan de meest recente studies, al weer uit 2005 een fase I studie en uit 2009 van een fase II studie eraan toegevoegd. Met ook opmerkelijk goede resultaten met deze niet toxische aanpak van hairy cell leukemie. Onderaan een link naar de volledig openbare studieverslagen en een referentielsijt.
d.d. 2 augustus 2003: Carla, een vrouw met HCLv vroeg informatie aan voor de BL22 trial en zou zonder meer toegelaten worden in een phase II trial, aldus Dr. Kreitman. De BL22 wordt in nog geen enkel ander land gegeven helaas want als je de resultaten leest is er best succes mee, ook bij Chronische Lymfatische Leukemie. Hier de antwoorden van Dr. Kreitman aan Carla die ook belangrijk kunnen zijn voor anderen.
Een vrije vertaling van antwoorden op een aantal vragen van Carla aan Dr. Kreitman:
1. Dr. Kreitman heeft uit 49 patiënten die zijn behandeld met BL22 afgelopen jaren slechts twee of drie HCLv patiënten behandeld. De andere patiënten hadden allemaal HCL (Hairycel leukemie ) of CLL (Chronische Lymfatische Leukemie.
2. U zult waarschijnlijk veel behandelingen met BL22 nodig hebben omdat HCLv moeilijker te behandelen is dan HCL.
3. U zult behandeld worden elke vier weken in ons ziekenhuis in Bethesda, Maryland. U zult voor elke behandeling 8 dagen in het ziekenhuis verblijven. (bv. een van onze HCLv patiënten is op dit moment al voor de 27e keer (week) terug voor een behandeling.
4. Tussen de behandelweken door zult u per keer drie weken thuis kunnen zijn of bij iemand anders in Amerika. We zullen u op 'outdoor' basis begeleiden en elke twee/drie dagen zal een verpleegkundige u bellen en u zult minstens elke week een bloedtest moeten doen terwijl u niet in het ziekenhuis, dus 'outdoor' patiënt bent.
5. Het NCI maakt geen verblijfsreserveringen voor patiënten tussen de behandelweken door. U moet uw eigen verblijf zelf regelen. Ik stel voor dat u uw ambassade kunt vragen te bemiddelen.
6. We hebben van geen enkel sterfgeval gehoord onder de 49 patiënten die inmiddels met BL22 zijn behandeld.
7. Er doet zich geen misselijkheid of overgeven voor wegens het medicijn BL22. Er heeft zich wel een vorm van niervergiftiging voorgedaan maar dat was in de vier gevallen behandelbaar. Andere bijwerkingen kunnen zijn: jeuk, vermoeidheid, koorts bij sommige patiënten en spierpijn. Niet alle patiënten hebben deze bijwerkingen.
8. U kunt de BL22 behandeling krijgen hier op het NCI in Bethesda, Maryland, USA. Helaas kan deze behandeling niet elders worden gegeven.
Hier de originele tekst van dr. Kreitman:
Dear ....., I will do my best to answer your questions:
1. Dr. Kreitman will have to answer you regarding results on HCLv patients. I will ask him to respond to your questions. We have only treated 2 or 3 HCLv patients out 49. The other patients have had HCL or CLL.
2. You will most likely need many treatments with BL22 because HCLv is more difficult to treat than HCL.
3. You will need to be treated every 4 weeks here in our hospital in Bethesda, Maryland. You will be in the hospital 8 days for each treatment. (Example: one of our HCLv patients currently being treated has come back 27 times (weeks) for continued treatment. 4. There are 3 weeks between each treatment during which time you will be at home or staying with someone here in the United States. We will continue to monitor you on an outpatient basis. Our nurses will telephone you ever 2 or 3 days, and you will have to have blood tests done at least once a week while you are an outpatient. 5. The National Cancer Institute does not make housing arrangements for patients between treatments. You must make your own arrangements. I suggest you contact your embassy for assistance. 6. We have not seen hearing loss with 49 patients receiving BL22. 7. There is no nausea and vomiting with the drug. We have had some kidney toxicity, but this was reversable in 4 patients. There was no permanent damage. Other side effects may include rash, feeling tired, fever in some patients, muscle aches. Not all patients experience these side effects. 8. You can only receive BL22 here at the National Cancer Institute, Bethesda, Maryland, USA. Unfortunately, the drug cannot be given anywhere else. I hope these answers are helpful to you. Please let me know if you have further questions. Sincerely,
Karen d.d. mei 2001: Eiwit geeft hoopvolle resultaten in bestrijding van zeldzame vorm van leukemie Van een trouwe bezoeker van deze site kregen we het volgende bericht. (En inmiddels een tweede artikel daaronder) Het is weliswaar slechts een Phase I studie en ook nog bij een zeldzame vorm van leukemie, maar de resultaten zijn zo opmerkelijk dat we dit toch hier willen melden. Ook omdat dit eiwit in de Phase II studie getest gaat worden bij non-Hodgkin patiënten en bij andere vormen van leukemie.
d.d. 21 oktober: inmiddels hebben we gehoord (via zoektocht van Marina en Cor, de ouders van Shifra) dat met dit BL22 al Phase III studies aan de gang zijn en binnen twee jaar wordt verwacht dat deze vorm van immunotherapie standaard gegeven mag worden bij o.a. ALL. Een Nederlandse professor werkzaam in Utrecht is hier bij betrokken. Hieronder het Engelse persbericht en beschrijving van twee eerdere trials.
NEW ORLEANS, March 27, 2001 -- Early tests in humans of a new compound show promising results for patients with a rare form of blood cancer say researchers at the National Cancer Institute.
In an early clinical trial designed only to test safety of the drug, a protein-based compound called BL22, produced complete remissions in a high percentage of patients with hairy cell leukemia (HCL) resistant to standard therapy. The research team led by Dr. Robert Kreitman, chief of the Clinical Immunology Section, Laboratory of Molecular Biology at the NCI presented the preliminary data at the American Association for Cancer Research meeting here.
"With our longest follow-up at 15 months, the research is still in its early stages," said Kreitman in a prepared statement. "But with several patients having maintained complete remissions for more than a year, BL22 appears promising as a treatment for patients who do not respond fully to first-line therapies."
Hairy cell leukemia is a disease in which cancer (malignant) cells are found in the blood and bone marrow. The disease is called hairy cell leukemia because the cancer cells look "hairy" when examined under a microscope. HCL represents 2 percent of all leukemias, with 600 new cases diagnosed annually in the United States.
The research team at the National Cancer Institute (NCI) tested BL22 against several types of blood cancer. Of the 14 patients with HCL who completed treatment, 11 had no pretreatment antibodies to the drug, immune system proteins that would have neutralized its effect.
Patients received one to nine 3-week cycles of BL22 at the treatment regimen's higher doses. All 11 anti-body-free patients achieved complete remission, and no relapses occurred at a median follow-up period of seven months. Although side effects were usually mild and cleared on their own, several HCL patients had potentially serious side effects including swelling and hemolytic uremic syndrome -- a condition involving rupture of red blood cells, anemia, low platelet count, and kidney failure - all of which resolved.
BL22 is a protein compound created by the fusion of two components: a fragment of a monoclonal antibody and a fragment of a toxic substance manufactured by Pseudomonas bacteria. The monoclonal antibody fragment binds to CD22, a protein present on the surface of leukemia cells, which allows entry of the toxic fragment into the leukemia cell. Inside the cell, the toxin splits off and exerts its lethal effect, killing the malignant cell.
BL22 was developed at NCI for preclinical use by Kreitman; Dr. David
Fitzgerald, chief of the Biotherapy Section at the Laboratory of Molecular Biology; and Dr. Ira Pastan, chief of the Laboratory of Molecular Biology.
Since the early 1990s, two standard treatments for HCL have been available, each with a high rate of complete remission (70 percent to 85 percent) in previously untreated patients. However, various studies have found a 13 percent to 50 percent incidence of residual disease after use of these therapies. In the BL22 study, sensitive tests detected malignant cells in blood, bone marrow, or elsewhere in only one (9 percent) of the patients in complete remission.
According to Kreitman, an important characteristic of the responding patients was the absence of pre-existing antibodies to the Pseudomonas toxin, which might develop after exposure to the bacteria, possibly through something as simple as a cut, and neutralize the cancer-killing effect of the drug. Some 5 percent of the population has significant levels of antibodies to Pseudomonas. Even after treatment with BL22, however, most leukemia patients do not develop the antibodies.
Among the 29 patients who finished treatment, complete responses were seen only in the HCL group. Partial or marginal responses occurred in patients with chronic lymphocytic leukemia (CLL), and responses improved with additional treatment cycles.
The NCI team expects to complete the phase I trial of BL22 and begin enrolling patients for multi-center phase II trials this year. In these upcoming safety and efficacy studies, BL22 will be investigated in several trials, including one for HCL and others investigating its use in CLL, non-Hodgkin's lymphoma, and pediatric leukemias.
American Association for Cancer Research (AACR) press release from the Annual Meeting, Mar. 24-28, 2001, New Orleans, La.
Een ander artikel over dezelfde aanpak met BL 22 is de volgende:
Scientists Report Complete Remissions in Early Leukemia Trial
To read a detailed interview with Drs. Pastan, Kreitman, and FitzGerald about this study, please go to: http://newscenter.cancer.gov/behindnews/hairyjuly25
Scientists report today in the New England Journal of Medicine* that 11 of 13 patients with hairy cell leukemia, a cancer of the immune system, had complete remissions after receiving adequate treatment with the recombinant immunotoxin BL22. A recombinant immunotoxin is an antibody that has been bioengineered to recognize and directly deliver a deadly toxin to tumors, in this case, hairy cell leukemia cells.
According to the authors, this week's results are particularly impressive because the patients, all of whom failed previous chemotherapy, were treated in a Phase I clinical trial, an early study designed primarily to determine how to administer a drug, not cure the disease. Pastan said the two other patients in the study who received adequate treatment had partial remissions, and they continue to receive BL22.
"We expected that some patients would respond to the treatment," said Ira Pastan, M.D., a senior author on the paper and leader of the National Cancer Institute's immunotoxin therapy group. "But we didn't imagine in our wildest dreams that almost all of the patients would go into complete remission. Half of the patients went into complete remission after a single cycle of treatment, and that was exciting to see."
Pastan said BL22, developed in the laboratory jointly with NCI scientists
Robert J. Kreitman, M.D., and David J. FitzGerald, Ph.D., was licensed over a year ago to AlbaPharm, Inc., of Rockville, Md. The company, in collaboration with Pastan's group, is now planning a larger clinical trial with the immunotoxin that will involve hairy cell leukemia patients from throughout the country. Hairy cell leukemia, or HCL, is diagnosed in about 700 Americans each year, accounting for about 2 percent of all leukemias.
This week's results were highlighted last April during a presentation at the annual meeting of the American Association for Cancer Research.
According to Kreitman, the principal investigator of the clinical trial and a senior author on the paper, BL22 is made by cloning portions of antibodies to portions of a toxin secreted by the bacteria Pseudomonas aeruginosa. "Recombinant DNA techniques allow cloning part of the antibody and part of the toxin to make a smaller recombinant immunotoxin that gets into the tumor faster and reduces the toxicity to the body," said Kreitman.
The antibody portion of BL22 specifically binds to the CD22 receptor, which is found in abundance on the surface of many types of leukemia cells. CD22 is also found, in lower amounts, on the surface of normal B cells. Therefore, it seems likely that BL22 would bind to and destroy both leukemic cells and normal B cells. Because stem cells––the progenitors of normal B cells––do not have CD22, any B cells lost in the short-term treatment should be replaced by the patient's untouched stem cells. And, in fact, Kreitman and his colleagues did not detect a decrease in normal B cells of patients.
Kreitman added, "Malignant stem cells–– the progenitors of the leukemic cells--may be CD22-positive as well and be lost, too. But only further follow-up will determine if this is correct." Therefore, it is thought that this treatment may not only clear the body of malignant circulating cells but may remove the source of the cells, the malignant stem cells.
The most serious side effect of BL22 immunotoxin treatment was a decrease in platelet and red blood cell counts. This decrease was associated with the clotting and breaking up of red blood cells in the kidney, which can cause kidney failure. However, both patients experiencing the side effect completely recovered and had complete remissions of HCL. Using a modified method of BL22 administration, this side effect was not detected in many patients treated later in the study.
It is possible that the BL22 immunotoxin will prove to be useful in treating more than just hairy cell leukemia. The Phase I trial includes patients with other types of leukemia and, while Kreitman and his colleagues saw the most dramatic response in HCL, a significant benefit was seen in chronic lymphocytic leukemia. These leads are being followed up by the researchers. "The hairy cell leukemia cells have more CD22 receptors and therefore respond faster and more thoroughly than the other cancers being investigated," Kreitman explained.
BL22 was well tolerated and highly effective in HCL, even after one cycle
Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies.
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bldg 5124b, 9000 Rockville Pike, Bethesda, MD 20892, USA. email@example.com
To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin.
PATIENTS AND METHODS:
Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 microg/Kg every other day x 3 doses.
BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at > or = 40 microg/Kg every other day x 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 microg/Kg IV. QOD x 3. The most common toxicities at 30 to 50 microg/Kg every other day x 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema.
BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response.
- [PubMed - indexed for MEDLINE]
BL22 activity in HCL is confirmed. Best responses to BL22 after cladribine failure are achieved before the patients develop massive splenomegaly or undergo splenectomy
Phase II trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with hairy cell leukemia.
Laboratory of Molecular Biology, Laboratory of Clinical Pathology, and Medicine Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. firstname.lastname@example.org
To conduct a phase II trial in chemoresistant hairy cell leukemia (HCL) with BL22, a recombinant anti-CD22 immunotoxin which showed phase I activity in HCL.
PATIENTS AND METHODS:
Eligible patients had relapsed/refractory HCL and needed treatment based on blood counts. Patients were stratified into three groups: response to cladribine less than 1 year, those with a response lasting 1 to 4 years, or no response and uncontrolled infection. Patients received BL22 40 microg/kg every other day for three doses on cycle 1. Those achieving hematologic remission (HR), defined as neutrophils > or = 1,500/mm(3), hemoglobin > or = 11 g/dL, and platelets > or = 100,000/mm(3), were observed. Patients without HR were re-treated at 30 microg/kg every other day for three doses every 4 weeks beginning at least 8 weeks after cycle 1.
Thirty-six patients were enrolled including 26, nine, and one in groups 1 to 3. The response after one cycle (CR, 25%; PR, 25%) improved when 56% were re-treated (CR, 47%; PR, 25%). CR rate was similar in groups 1 and 2 (P = .7). Twenty-two with baseline spleen height lower than 200 mm had higher CR (64% v 21%; P = .019) and OR rates (95% v 36%; P = .0002) compared to 14 with spleens either absent or higher than 200 mm. The only serious toxicity was reversible grade 3 hemolytic uremic syndrome, not requiring plasmapheresis, in two patients (6%). High neutralizing antibodies were observed in four patients (11%) and prevented re-treatment.
BL22 activity in HCL is confirmed. Best responses to BL22 after cladribine failure are achieved before the patients develop massive splenomegaly or undergo splenectomy.
- [PubMed - indexed for MEDLINE]
- PMCID: PMC2702232
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