Perspectives

Conclusions from abstract:

1) Approximately 50% of all DLBCL patients in this northern US latitude population are vitamin D deficient at the time of diagnosis and treatment.

=> That part is not surprising since vitamin D deficiency is equally common in the general population as described here: "Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults and up to 57% of general medicine inpatients in the United States and in even higher percentages in Europe. Recent epidemiological data document the high prevalence of vitamin D inadequacy among elderly patients and especially among patients with osteoporosis. " Source: http://www.ncbi.nlm.nih.gov/pubmed/16529140

2) Vitamin D deficient patients [in these samples] have an inferior event-free and overall survival compared to patients with vitamin D levels within the normal range.

=> This part is intriguing and begs the questions: A) is this in part coincidental, or B) does higher-risk DLBCL decrease serum levels of vitamin D - making it a useful marker to identify high-risk DLBCL? (i.e., is it influenced by a genetic factor in these patients) ... or C) does having a deficiency in Vitamin D contribute to resistance to treatment, which might be remedied in part with supplementation? -- The latter possibility has to be asked cautiously in a clinical trial -- with careful monitoring to avoid the known risks of vitamin D supplementation in lymphoma survivors.

Conclusion: Expect that the Vitamin industry to exploit this report to promote the sale of vitamin D to lymphoma patients, despite the known risks of Vitamin D supplementation in this population ... and the lack of data showing that supplementation could improve the outcome.

H1N1 vaccination – Controversies and Myths 10/09

At issue is the safety of H1N1 vaccine (injection of dead virus antigens) to prime our immune systems against a virulent live virus.

Instead of applauding the response time in testing and developing a vaccine to protect us from a virus that can kill, we have wide-spread mistrust about the safety of the remedy, even though the process for creating the H1N1 vaccine is reported by experts to be the same as for other flu vaccines.

What inflames the issue is that our assumed "right" to make independent decisions can put others (our children) at greater risk ... that is, the ability to control an infectious disease - preventing its rapid spread - requires that we work as a community and are vaccinated.

The uncertainty or controversy seems to be really about lack of trust in our public agencies, in this case the CDC (Center for Disease Control) and the FDA ... Which I think speaks to our failure to effectively communicate how they operate; but also a lack of commitment to address misinformation and myth, which then percolates on the airways and Internet ... becoming the "truth" in large segments of the public.

... For example, the false belief (the toxic idea) that childhood immunizations cause autism. Although scientists have not identified any evidence to support this belief, the myth lives on:

So it comes back to a familiar topic of discussion for cancer survivors ... that an association (an observation that an action occurred before an event) is not evidence of causation (that the action caused the event), and that knowing the difference can be a vital public health matter.

"There are about 2,400 miscarriages a day in the U.S.," said Dr. Jay C. Butler, chief of the swine flu vaccine task force at the federal Centers for Disease Control and Prevention. "You’ll see things that would have happened anyway. But the vaccine doesn’t cause miscarriages. It also doesn’t cause auto accidents, but they happen." 3

I don’t think the lay public is aware that the CDC and FDA operate with evidence-based standards. That's not to say these government agencies are immune from error, but it’s important to recognize that the decisions made here (as directed by Congressional legislation) are science- and peer-based, not based on individual opinion, or by partisan or profit motives.

-- However being government agencies it appears that they are associated in the public mind with how other political decisions are made -- with too many instances of policy corrupted by special interests.

Reply to inquiry: What about Guillain-Barre syndrome, associated with the 1976 swine flu?

Slamming the Umpire - comment on advocacy that demonizes the FDA (Sept 18, 2009)

Re: NY Times article: Where Cancer Progress Is Rare, One Man Says No http://bit.ly/4Bppb2

I think that reviewers at FDA work conscientiously to make the right call ... but that its public image suffers in part because it's not permitted to disclose its reasons for rejecting or accepting a new drug application.

-- Noting that it was the industry that lobbied for non-disclosure rules ... the rationale being the protection of intellectual property. A questionable concern as evidenced in any Advisory Committee review -- conducted transparently to address the main issues with the submitted study data -- with no apparent harm to the drug sponsors.

This is NOT to suggest that the agency always gets it right, or that the reviewers are always experienced enough with all aspects of the medical condition (have the context right or the correct interpretation of the data) ... or that informed patient perspectives are not needed to help make these difficult decisions.

(Typically the assessment is complex. The new drug can harm some patients while benefiting others, or the benefit is modest relative to existing care. Critical to assessment is the net effect, including the clinical significance of the responses, weighed against adverse events and what is already available as therapy.)

However, mistrust with the review process should be expected when the raw data is not published in the public domain ... leaving the community to see only the biased interpretations of the sponsors, and, yes, sometimes the investigators as well. The agency, as noted above, by law, can say nothing to defend its decision.

I suspect that a rationale for aggressive patient advocacy against FDA is based on an assumption that what worked for early HIV activists (creating needed regulatory change at that time) is still needed today, or that the AIDS activists formula for success will lead to similar results in any medical conditions?

But diseases (heart disease, AIDS, cancers) can have very different potentials to be effectively treated, dependent on the underlying nature of it, and technologies that can effectively and safely target disease processes. Progress against some diseases will take decades, others years, even if given the same effort - and it may be that some diseases will never be cured.

(Fortunately experts say, and evidence shows, that the blood cancers are not among these!, but in general it has proven more difficult to safely treat cancers than most viruses.)

Meanwhile the FDA review process is widely accepted as efficient and fair within the industry and among mainstream investigators. And if the agency was not fair, was arbitrary in its decision process, why would any company invest so much to develop and test new drugs for disease? That a good number of new drugs for cancers are approved rapidly by FDA, should be evidence of the agency's intent?

Clearly, aggressive advocacy is needed, always, to maintain or create a sense of urgency. But it's misplaced if its purpose is to demonize the FDA or individuals that lead it - who are, by the way, also impacted by cancers, sometimes directly.

(Remembering our beloved colleague, Pattie Delaney http://www.patientadvocate.org/news.php?p=613 )

Instead advocates should work to raise awareness that studies testing urgently needed new cancer agents are starving for participants. Many never completing enrollment. Today's count: 1,226 studies actively recruiting patients for the treatment of lymphoma and CLL.

Regarding ABT-263 - a Dose Finding Study
(Sept 17, 2009)

Click here to provide comment by e-mail.

As you may know, dose finding studies are essential to the development of any new agent .. to identify the dose of a drug that achieves sufficient levels in the blood to have a treatment effect (causing tumor cells to die), which will invariably also have side effects -- i.e., causing also some types of normal cells to die, for example, in this case, platelets which are likely renewable. See also What's a Drug

-- The objective being to find a dose that is active but also has acceptable toxicity - the so-called therapeutic window. Phase II studies will then test for signals of efficacy and safety at that dose.

Quiz: So which doses will be chosen based on the signals of activity and toxicity in the study below? For CLL? For Lymphoma?

Tip: Peek at the study protocols recruiting below.

Time will tell, but the answers are totally dependent on the warriors among us who participate in the clinical trials. How else?

==
* Clinical trials recruiting: ABT-263 in lymphoma and CLL http://bit.ly/28gS7e by location (State): http://bit.ly/1446Kx

==
* Report on dose finding: ABT-263 activity and safety http://bit.ly/C4duG copying:

ABT-263, a novel, orally bioavailable, BH3 mimetic, binds with high affinity (Ki ≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins.

ABT-263 displays ... Mechanism based preclinical toxicities include reductions in circulating lymphocytes, apoptosis of circulating platelets, and decreased spermatogenesis, mediated by inhibition of Bcl-2, Bcl-XL, and Bcl-w, respectively.

ABT-263 in 2 enrolling phase I studies in relapsed/refractory lymphoid malignancies (M06-814) and CLL (M06-873) was evaluated.

Patients (pts) were dosed on days 1-14 of a 21 d(ay) cycle, 10-440mg (M06-814) or 10-250mg (M06-873).

Continuous 21/21 d dosing (CD) post lead-in dose is being explored in both studies.

Results:

55 pts, 14/21 d(ay) dosing, enrolled in the 2 studies.

ABT-263 PK were linear from 10 - 440mg (N=55); terminal half-life was 14 - 20 h (n=35).

Among 27 CLL/SLL pts , 3 have confirmed radiographic partial responses (PR) (99%, 92% and 72%) and 2 have unconfirmed regressions, 51% and 72%. 6 pts maintained a ≥50% decrease in circulating lymphocytes for ≥ 2 months and 11 pts have stable disease ; of these 5 experienced minor radiographic responses (range of 36% to 49%).

In addition, among 40 (M06-814) lymphoma pts, 3 with follicular lymphoma achieved PR and one had a minor response (49% regression). With CD dosing (16 pts), activity includes 1 unconfirmed PR in SLL & and 3 CLL pts with ≥50% lymphocyte reduction for ≥2 months duration.

Pharmacodynamic toxicities included dose-dependent thrombocytopenia (TCP) resulting from on-target activity against Bcl-XL.

Dose limiting toxicities, 14/21 d dosing,

in M06-814 (lymphoma) occurred at

160mg (bronchitis),
315mg (elevated ALT and grade 4 TCP) and
440mg (worsening pleural effusion in a pt with underlying afib),

and in M06-873 (CLL study) at
110mg (tumor lysis and grade 4 TCP) and
250mg (grade 4 TCP).

Conclusions: ABT-263 showed favorable PK and safety profiles with anti-tumor activity in relapsed/refractory CLL/SLL and follicular lymphoma. Identification of optimal dose and schedule for phase II trials continues.

As you may know, FDA will seek the advice of an advisory committee (a panel of independent experts) to help it decide if outcome data submitted to it for marketing approval is sufficient. Typically FDA only asks for such guidance in a close call or when there are issues with study methods or outcome interpretations.

Yesterday, two new lymphoma drugs were reviewed by committee: (1) Romidepsin for relapsed advanced cutaneous t-cell lymphoma (CTCL), and (2) Pralatrexate for aggressive relapsed Peripheral T-Cell Lymphoma (PTCL) ... It was an honor to take part as patient representative in each deliberation.

For Romidepsin (CTCL) there was little controversy reflected in the 10 - 0 vote in favor of full approval - not shocking given that it met its predefined primary endpoint (35% response rate), the responses were durable, and the safety was acceptable ... but also because the positive outcomes were replicated in two independent studies and the clinical course of advanced CTCL is predictable and there are no approved therapies.

However, in the afternoon session (in the review of Pralatrexate for PTCL) there was much controversy. A good number of experts (particularly Dr. Fleming, statistician, Univ. Wash) argued vigorously that the evidence was too thin, particularly for one single-arm study. However the majority on the panel felt there was sufficient evidence of benefit to support accelerated (conditional) approval given the predictable dire clinical path for this population.

-- I felt this was a significant outcome for any single agent drug in relapsed aggressive PTCL (cytotoxic combination therapy is generally used with poor overall results), and argued that a small subset (about 12 of 109) clearly benefited - had durable responses (range 196 to 535+ days) ... which helped some of these patients to "bridge" to transplant. This, to me, is clear evidence of clinical benefit, even if in a very small subset - a small step in the right direction.

Summary of data (n=109):
   Activity: CR = 9, PR = 20 and Stable Disease = 24
   Mean durability of response was lower than anticipated:
      13 of 29 lasting 14 weeks or less
      however, 12 pts had durable responses
   1 pt had a possible treatment-related death; 7 deaths were from progressive disease

Other experts (mainly clinicians on the panel who treat lymphomas) noted that while many other available agents may be able to achieve a similar overall response rate of 27% in this population (an issue cited by Wyndham Wilson MD), that this study was the first to achieve that rate with independent validation and a relatively large population (n = 109). Further, it was helpful I think that pralatrexate is clearly an active drug with an acceptable safety profile, which has also a unique mechanism of action - cited also by Wilson as *urgently needed* for PCTL in the conclusion of his presentation.

... In my view, that Dr Wyndham Wilson voted in favor of approval -- despite raising the most challenging reservations with the data as it relates to existing options -- provides good assurance that the committee got it right, voting 10 versus 4 for conditional approval.

Ultimately, outcomes from drug interventions must be judged in the context of the natural course of the disease and available treatment options, but also the ability to do well-controlled studies, which is dependent on the incidence of the disease. My concern is that if the "bar" is raised too high in all circumstances that the rare medical conditions will just not be studied - ever. The consequence being that relapsed PTCL will continue to be fatal in almost all cases.

Karl Schwartz (Patient Representative)

Reports on same:

=in 10-0-1 vote, FDA expert panel recommends for FULL approval of Romidepsin (HDAC inhibitor) for cutaneous t-cell lymphoma based on response rate and duration of response in two single arm studies
http://bit.ly/G9ii0

=
In 10-4 vote, FDA expert panel recommends for ACCELERATED * approval of Pralatrexate (Folotyn) for relapsed PCTL* following a contentious discussion
based on response rate in one single arm study

See FDA Panel Supports Pralatrexate Application in Peripheral T-Cell Lymphoma http://bit.ly/1YkFhf

* PTCL comprises a biologically diverse group of aggressive blood cancers that has a worse prognosis than most other types of lymphoma, including B-cell lymphoma.

* an accelerated approval is based on a surrogate endpoint deemed reasonably likely to predict clinical benefit, such as response rate. Companies granted accelerated approvals are required to conduct confirmatory postmarketing studies to verify and describe the clinical benefit.

* pralatrexate - The drug aims to camouflage itself as a folic acid so it can be absorbed by the tumor, then attack the cancer.

About Lymphoma | Advocacy & Art | CAM & Life Style | Clinical trials | Docs & Centers | Guidelines at Diagnosis | How to Help | Side Effects | Support | Symptoms | Tests | Treatments | Types of Lymphoma

Vitamin D Deficiency Associated with Inferior Outcomes in DLBCL http://bit.ly/vit-D-survival

H1N1 vaccination – Controversies and Myths 10/09

Slamming the Umpire - comment on advocacy that demonizes the FDA (Sept 18, 2009)

Regarding ABT-263 - a Dose Finding Study
(Sept 17, 2009)

About Lymphoma | Advocacy & Art | CAM & Life Style | Clinical trials | Docs & Centers | Guidelines at Diagnosis | How to Help | Side Effects | Support | Symptoms | Tests | Treatments | Types of Lymphoma

Vitamin D Deficiency Associated with Inferior Outcomes in DLBCL http://bit.ly/vit-D-survival

H1N1 vaccination – Controversies and Myths 10/09

Slamming the Umpire - comment on advocacy that demonizes the FDA (Sept 18, 2009)

Regarding ABT-263 - a Dose Finding Study (Sept 17, 2009)

Regarding ABT-263 - a Dose Finding Study
(Sept 17, 2009)