Sunitinib brings Adult Acute Lymphoblastic Leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade
Curator: Aviva Lev-Ari, PhD, RN
Word Cloud by Daniel Menzin
Updated 11/13/2013
Pazopanib versus Sunitinib in Renal Cancer
N Engl J Med 2013; 369:1968-1970November 14, 2013DOI: 10.1056/NEJMc1311795
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To the Editor:
Cancer treatments are expensive. The estimation of the total cost can be challenging because of several factors such as efficacy, toxicity, and the costs and duration of supportive care and end-of-life care. Motzer et al. (Aug. 22 issue)1 report similar efficacy but a favorable safety and quality-of-life profile and less medical resource utilization with pazopanib as compared with sunitinib in first-line therapy for metastatic renal cancer. Since oncology is becoming an increasingly value-based specialty, we wanted to highlight another important aspect of this trial. Pazopanib appears to be favorable not only in terms of safety and quality of life, but also in terms of overall cost. A 30-day supply of pazopanib (at a dose of 800 mg daily) ranges from $3,500 to $8,556, whereas a 30-day supply of sunitinib (at a dose of 50 mg daily) ranges from $4,500 to $13,559.2 The total cost of pazopanib during the median progression-free survival of 8.4 months is $29,400 to $71,870, and the total cost of sunitinib during the median progression-free survival of 9.5 months is $42,750 to $127,454. Less toxicity and less medical resource utilization with pazopanib will most likely further lower the overall costs of treatment with this agent. Comparative-effectiveness trials hold great promise for maximizing patient safety, improving treatment outcomes, and reducing costs.
Ryan Ramaekers, M.D.
Mark Tharnish, Pharm.D.
M. Sitki Copur, M.D.
Saint Francis Cancer Treatment Center, Grand Island, NE
mcopur@sfmc-gi.orgNo potential conflict of interest relevant to this letter was reported.
To the Editor:
Motzer et al. report a combined analysis of two open-label noninferiority trials (927 patients in the original trial and 183 patients in a second trial), each of which compared pazopanib with sunitinib with respect to progression-free survival in renal-cell carcinoma. Quality-of-life outcomes were subjective.
Analysis of noninferiority trials is notoriously difficult.1,2 The authors’ analysis of the trials, which was open-label because of the different administration schedules of the drugs, presents problems in interpreting progression-free survival and quality of life. The studies define disease progression differently. The larger study defined progression-free survival according to independent review. The protocol for the smaller study states that progression-free survival “will be summarized . . . based on the investigator assessment.” Inference from subjective outcomes in unmasked trials (e.g., quality of life in both studies and progression-free survival in the smaller study and therefore in the combined analysis) is subject to well-known bias. Moreover, the article does not state how many of the 379 participants (34%) who discontinued the intervention before death or disease progression (see Fig. S2 in the Supplementary Appendix, available with the full text of the article at NEJM.org) were assessed for progression-free survival. A fair comparison must use rigorous methods to handle missing data.3 Since the article did not deal appropriately with missing data, its conclusions regarding noninferiority are uninterpretable.
Janet Wittes, Ph.D.
Statistics Collaborative, Washington, DC
janet@statcollab.comDr. Wittes reports that her company, Statistics Collaborative, has consulting agreements with both GlaxoSmithKline and Pfizer, the manufacturers of the drugs discussed in the article by Motzer et al. In addition, Statistics Collaborative has contracts with several other companies that produce drugs for patients with cancer. No other potential conflict of interest relevant to this letter was reported.
To the Editor:
Motzer et al. state that “the results of the progression-free survival analysis in the per-protocol population were consistent with the results of the primary analysis.” However, the predefined margin of noninferiority (<1.25) was not met. The upper limit of the confidence interval (1.255) was clearly above the defined threshold.1 In a noninferiority trial, the use of the intention-to-treat population is generally nonconservative,2 the full analysis set and the per-protocol analysis set are considered to have equal importance, and the use of the intention-to-treat population should lead to similar conclusions for a robust interpretation.3 Thus, it is surprising that the authors did not come to or discuss the same conclusions as that of the French National Authority for Health4: “serious doubt exists about the noninferiority result of pazopanib compared to sunitinib” and “the clinical significance of the noninferiority threshold defined in the protocol was an efficacy loss of 2.2 months in the median progression-free survival. This is too large for patients.”
Jochen Casper, M.D.
Silke Schumann-Binarsch, M.D.
Claus-Henning Köhne, M.D.
Klinikum Oldenburg, Oldenburg, Germany
casper.jochen@klinikum-oldenburg.deDr. Casper reports receiving consulting fees from Bayer, Novartis, and Pfizer and speaking fees from Novartis and Pfizer. No other potential conflict of interest relevant to this letter was reported.
The authors reply: In reply to Ramaekers et al.: we agree that decisions regarding the provision of health care include economic evaluations to identify treatments that provide the best clinical benefit at an acceptable cost.
To clarify a point in the letter by Wittes: the primary end point of this phase 3 trial was progression-free survival evaluated by an independent review committee; these data were assessed for all 1110 patients from both trials. This is specified in the protocol. The consistency of the quality-of-life results with the observed differences in the safety profiles for the two drugs speaks to the absence of bias in the quality-of-life outcome. The number of patients in whom follow-up ended before progression was assessed by the independent review committee was balanced between the two groups: 156 patients in the pazopanib group (28%) and 168 patients in the sunitinib group (30%). To Wittes’s final point regarding rigorous methods to handle missing data: the algorithm for assigning disease-progression and censoring dates followed the Guidance for Industry of the Food and Drug Administration1 and is included in the protocol of our article.
In reply to Casper et al.: there is no consensus regarding whether the per-protocol population is more conservative than the intention-to-treat population for the noninferiority analysis.2,3Reviews of noninferiority trials indicate that the per-protocol population is not generally more conservative than the intention-to-treat population, and there are scenarios in which the per-protocol analysis itself could introduce bias.3 A systematic review indicated that more than 70% of published findings from noninferiority trials in oncology show results in only the intention-to-treat population and not in the per-protocol population.4 Our phase 3 trial had a single primary analysis in the intention-to-treat population, with the per-protocol population included as a key sensitivity analysis, as supported by Fleming et al.5 No formal hypothesis testing was planned for the per-protocol population, nor was the trial powered for this. Consistency of the point estimates was desired to show an absence of bias due to the analysis population. This absence of bias was shown by the consistency of the hazard ratios (1.07 in the per-protocol analysis vs. 1.05 in the primary analysis). For an underpowered per-protocol comparison, it is inappropriate for Casper et al. to interpret that the upper bound that barely exceeded 1.25 in our per-protocol analysis is an indication of inconsistency of results across the two populations. The noninferiority margin was selected in consultation with oncology experts, and justification of the margin is in the protocol.
Robert J. Motzer, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY
motzerr@mskcc.orgLauren McCann, Ph.D.
Keith Deen, M.S.
GlaxoSmithKline, Collegeville, PASince publication of their article, the authors report no further potential conflict of interest.
REFERENCES
Food and Drug Administration. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. May 2007 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf).Jones B, Jarvis P, Lewis JA, Ebbutt AF. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996;313:36-39[Erratum, BMJ 1996;313:550.]
CrossRef | Web of Science | MedlineBrittain E, Lin D. A comparison of intent-to-treat and per-protocol results in antibiotic non-inferiority trials. Stat Med 2005;24:1-10
CrossRef | Web of Science | MedlineTanaka S, Kinjo Y, Kataoka Y, Yoshimura K, Termukai S. Statistical issues and recommendations for noninferiority trials in oncology: a systematic review. Clin Cancer Res 2012;18:1837-1847
CrossRef | Web of Science | MedlineFleming TR, Odem-Davis K, Rothmann MD, Li Shen Y. Some essential considerations in the design and conduct of non-inferiority trials. Clin Trials2011;8:432-439
CrossRef | Web of Science | MedlineSOURCE
Original Article Published on 7/9/2012
July 6, 2012 NY Times reports on a new approach based on DNA and RNA sequencing and a cancer drug for kidney cancer to bring REMISSION to Adult acute lymphoblastic leukemia (ALL).
On the lower left corner of this page – Watch the VIDEO
Dr. Lukas Wartman, is a Cancer Researcher specializing in Leukemia. He suspected he had Leukemia, the very disease he had devoted his medical career to studying.
After years of treatment and two relapses of ALL, he has exhaused all conventional approaches to his disease. At Washington University in St. Louis, his colleagues in the lab, decoded Dr. Wartman’s genetic information by genome sequencing techniques t determine the genetic cause of his ALL. The team found an overactive gne, FLT3 on Chromosome 13. The gene was treated with pfizer’s Suntinib drug for advanced kidney cancer.
Blood samples free of ALL found in days after using the drug. As results were very promising, Pfizer, the drug’s maker who has turned down Dr. Wartman’s request for the drug under their compassionate use program, though he explained that his entire salary was only enough to pay for 7 1/2 months of Sutent (Suntinib). While he does not know why Pfizer gave him the drug finally, he suspects it was the plea of his Nurse Practitioner, Stephanie Bauer, NP.
Identification of the genetic cause for his ALL, thus discovering a breakthough in understanding and treatment for ALL in other patients, involved the following steps:
SAMPLE
two tissue samples taken from Dr. Wartman’s Bone marrow and skin cells
SEQUENCE
Extracts of DNA and RNA from Dr. Wartman’s cells, two types of genetic material tested
COMPARISON
DNA sequesnces showed genetic mutations possibly related to his ALL, none seemed treatable. However, RNA sequencing revealed that a normal Gene, FLT3, on cheomozome 13, was overactive in his leukemia cells
TARGETING
The FLT3 gene helps create new white blod cells in the bone marrow. Dr. Wartman’s marrow bone cells were covered with an extreme number of FLT3 receptors which possibly caused the growth of his leukemia.
TREATMENT – Receptor Blockade
Drug known to block FLT3 receptor, Sunitinib, used for kedney cancer treatment, was given to Dr. Wartman. Two weeks after Dr, Wartman began taking the drug, tests revealed that his leukenia was in remission.
NEW MARKETS FOR FLT3 GENE BLOCKADE DRUG – KIDNEY CANCER AND LEUKEMIA
Pfizer has NOW a NEW market for Sunitinib — All CANCER PATIENTS DIAGNOSED WITH Adult acute lymphoblastic leukemia (ALL) where an overactive FLT3 gene on chomosome 13 is found.
NEW TREATMENT OPTIONS FOR Adult acute lymphoblastic leukemia (ALL)
Thus, any (ALL) diagnosed patient needs to be tested for Chromosome 13, ONLY rather then the entire genome sequencing of the Patient. If FLT3 is not found overactive, THEN proceed with entire genome sequencing of the Patient. IF another gene is overactive FIND DRUG FOR RECEPTOR BLOCKADE.
SIZING THE MARKET FOR FLT3 BLOCKADE DRUGS: KIDNEY CANCER vs LEUKEMIA
The Market for Adult ALL is much bigger than the market for kidney cancer. Thus, this discovery regarding the remission of Dr. Wartman’s remission following two relapses is so significant for Pfizer and for any patient with the diagnosis of Adult ALL.
I recommend the reader to click on the links and follow the reactions of the public to this article in The New York Times.
Read HUNDREDS of Comments by Cancer Patients and the readers of The New York Times Health Section
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An amazing story of how genome could give valuable cues for treatment and examples like these emphasize the importance personalized medicine is. Had it not been the detection of overactive FLT3 gene, it would have been impossible to save Dr. Wartman. Although expensive at this point (whole genome sequencing of an individual), it might get cheaper and ultimately provide therapy for cancer on individual basis.
Ritu, please note that FLT3 gene is on chromosome 13, any other ALL diagnosed patient, a lab can sequence only chromosome 13, If overactive use this drug that is blocking the receptor FLT3. if not over active start sequencing the entire Genome. Please note, for that very Post, I run 4 posts targeted for 4 different audiences. Try to do that with Mito one title disease driven, one metabolic, one therapeutic. Grabbing attention drives VIEWS and Comments.
Thank you for reviewing the post on ALL.
we need contact with Dr. Lukas Wartman, We live in Uruguay and have a son with LLA and 3 relapsed. We need help for him urgent
Dr. Lukas Wartman
Washington University
St. Louis, MO
4921 Parkview Pl
Saint Louis, MO 63110
(314) 747-1171 (Office)
(314) 362-3192 (Fax)
http://www.youtube.com/watch?v=gicm7kSd32Q
I highly recommend to talk to him and consider bringing your child to the Department of Oncology at either Dana Farbers in Boston or the Department of Pediatric Oncology Washington University St. Louis, MO – after consultation with Dr. Wartman.
Good Luck
Aviva Lev-Ari, PhD, RN
Did you have a e:mail of Dr Wartman?
I recommend you to CALL, you have an URGENT need for attention, e-mail is NOT the mode of communication.
I encourage you to call him as well as to contact Dana Farber in Boston, part of Children’s Hospital in Boston.
CALLING is the ONLY way to expediate attention.
Good Luck,
Aviva
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette