Date: December 22, 2006
by Chaya Venkat
Other Articles on: Meetings & Conferences
Editor's Note: These Highlights provide an overview of the research reported at the 2006 Annual Meeting of the American Society of Hematology. We will be publishing articles on additional subjects in the coming weeks.
One of the interesting poster presentations from the Mayo Clinic dealt with the scary subject of secondary lymphoid cancers (“LPD” or Lympho-Proliferative Diseases). Their analysis is based on a large and well characterized group of CLL patients in the Mayo Clinic database — and therefore the patterns observed are more robust than your average run-of-the-mill reading of the tea leaves. For you type A personalities who are prone to hit the CLL hard with the most aggressive therapy available to you as soon as you are diagnosed, I suggest you take a good hard look at this analysis. Secondary lymphomas in CLL patients are not good news. Median survival statistics for people who undergo Richter’s transformation are measured in months, not years, and these folks have drastically reduced therapy choices. Below are the major findings of the Mayo study. You may want to browse the Mayo Clinic poster (Second Malignancies Poster) to get the full flavor of the results reported.
Moral of the story: Watch & Wait is not such a bad deal compared to early treatment, especially if the “gold standard” (not!), fludarabine, is your therapy of choice. When it is time to treat, chose your poison carefully! Here are links to a couple of additional articles on our website you may wish to read regarding fludarabine: Fludarabine Monotherapy Is No Longer the Gold Standard; RF Risks and Rewards; Dawn of a New Era.
Those of you who follow our clinical trial reviews closely will no doubt remember the flap regarding combination of mitoxantrone with the FCR protocol (fludarabine, cyclophosphamide, Rituxan), a phase-2 trial initiated at M. D. Anderson early this year. We worried about the potential for cardiac toxicity in this aggressive regimen (courtesy of mitoxantrone), especially since the original schema for the trial made no mention of screening for cardiac sufficiency, or for counseling patients about the potential cardiac risks involved. We brought our concerns to the attention of their Principal Investigator, and we are happy to say the inclusion criteria were later modified to address our concerns (Mitoxantrone plus RFC, More on Mitoxantrone plus RFC, FMC plus R - Brit Version).
There seems to be a trend to ever longer alphabet strings of drug combinations, with toxicities to match, in treating CLL patients. I suppose beggars cannot be choosers, and cancer patients will swallow hard and tough it out with aggressive therapies, if the risks are worth the reward. You will therefore understand that we were very interested in how this four-drug combination of FCR + M worked out for the 29 intrepid volunteers who participated in this trial. Actually, that is a five drug combination since GM-CSF was given to all patients to protect against cytopenias. All of the patients were chemo-naïve and this was front-line therapy for all of them.
As expected, FCR + M + GM-CSF produced high response statistics. This was not a surprise, since we already knew that FCR by itself gives pretty high response statistics, without the added benefit of mitoxantrone. The million dollar question was the cost end of the equation. What was the cost of the expected high response rate, in terms of deep-seated neutropenia, infections and the like? The abstract below outlines the results the researchers saw — and our take on the results follows.
The NCI has a grading scale of 1 through 4 for measuring the seriousness of infections and cytopenias. Grade-1 is nothing much to write home about, Grade-2 should not be ignored, I would personally say “uncle” at Grade-3 and Grade-4 will most likely put you in the hospital. Keeping that in mind, an impressive 77% of the patients had Grade-3 or higher neutropenia, and another 20% had similarly high grade anemia and thrombocytopenia. The very high rates of high grade neutropenia are all the more disturbing since protective GM-CSF (trade name “Leukine”) was given to all the patients during each and every cycle and this should have helped prevent neutropenia. It appears this precaution was not sufficient in this clinical trial combination. Infections were seen in 45% of the patients. Also of concern to this reporter, no mention was made of any cardiac monitoring. Does this mean the news is good, no one had cardiac problems, or does it mean it was not measured and/or not reported? Given the track record of mitoxantrone on cardiac toxicity, I hope these patient volunteers will be monitored for a at least a couple of years after the completion of the trial.
Clinical trials are done to answer questions to which we do not know the answers. The question being asked in this clinical trial was this: would there be better response statistics deriving from the addition of mitoxantrone to the already potent FCR combination, and would we get the hoped for improvement in response without having to pay additional price of neutropenia, infection and the like, by means of adding the protective prophylaxis of GM-CSF across the board? The authors' conclusion below is pretty blunt, and I concur with it whole heartedly: no big improvement in response, and a whole lot more toxicity in terms of cytopenias.
Negative results in clinical trials are every bit as important as positive results, in fact sometimes they are even more important. How will we know what does not work, accept by actually doing pilot trials such as this? I give full credit to the researchers involved for prompt publication of these results. By the way, we discussed a potential trial using the same four drug combination FCR + M in the UK (see FMC plus R - Brit. Version), with slight differences such as recruiting previously treated and relapsed patients. Rumor has it this UK trial will not take place now — that it was turned down by their ethics review board. I think it is safe to say this particular combination (FCR + M + GM-CSF) will not be seeing much action in the near future, especially for chemo-naïve patients who have clearly better options available to them.
Fludarabine, Cyclophosphamide, Mitoxantrone Plus Rituximab (FCM-R) as Frontline Therapy for CLL: Results of a Phase 2 Study.
Session Type: Poster Session, Board #65-III
Stefan Faderl, William G. Wierda, Susan O'Brien, Alessandra Ferrajoli, Farhad Ravandi-Kashani, Michelle Detry, Hagop M. Kantarjian, Brandi O'Neal, Michael J. Keating
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Biostatistics Applied Mathematics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Combinations of monoclonal antibodies (moabs) with chemotherapy have produced higher rates of complete remission (CR) and better quality of responses (minimal residual disease [MRD]-negative) than have been achieved with chemotherapy or moabs alone. We have previously shown an overall response (OR) rate of 95% with a CR rate of 73% when combining fludarabine, cyclophosphamide, and rituximab (FCR) as first-line treatment for symptomatic patients with CLL (Keating et al. J Clin Oncol 23:4079; 2005).
Recent reports of FC plus mitoxantrone (FCM) have demonstrated response rates of 60% and up to 88% in pts with relapsed and untreated CLL, respectively. Here we report preliminary results of a pilot study exploring FCM plus rituximab and pegfilgrastim as frontline therapy for pts with untreated and symptomatic CLL and b2M < 4 mg/L.
Treatment consisted of F 25 mg/m2 i.v. d2-4, C 250 mg/m2 i.v. d2-4, M 6 mg/m2 i.v. d2, and R 375 mg/m2 i.v. d1. Pegfilgrastim was 6 mg s.c. d4. For courses 2-6, FCM started day 1 together with R 500mg/m2, and pegfilgrastim on d3. Courses were repeated q4-6 wks. The primary objectives included efficacy [clinical response by NCI-WG criteria and based on 2-color flow (CD5/CD19) response rate at 3 and 6 mos] and toxicity (especially myelosuppression).
Thirty-one pts were enrolled of whom 29 pts are evaluable for response at 3 mos, and 21 pts at 6 mos (1 pt was taken off for insurance reasons after one course, and 1 did not receive any
therapy). The median age was 57 yrs (range 38-69). Fourteen pts (48%) were male. Four pts (14%) had Rai stage 3. Median b2M was 2.6 mg/dL (1.4-4) and the median WBC 59.9 x 109/L (5.6-355). Two pts had 11q23 and 17p- abnormalities by cytogenetics/FISH. Unmutated IgVH occurred in 12/17 (71%) pts; ZAP-70 immunohistochemistry was positive in 11/19 (58%) pts.
Twenty-eight pts (97%) responded at 3 mos (41% CR, 17% nPR, 39% PR); 10 pts (34%) had <1% CD5/CD19+ cells in the marrow. Response rates at 6 mos: 33% CR, 10% nPR, 57% PR for an OR rate of 100%. Nine pts had PR because of persistent cytopenias without marrow involvement or residual lymphadenopathy. Eleven pts (55%) had < 1% CD5/CD19+ cells in the marrow at 6 mos. Grade >/= 3 neutropenia occurred in 77% of the pts, thrombocytopenia in 7%, and anemia in 13%. Infectious episodes were seen in 13 pts (45%). Of 21 pts who completed therapy, 3 have received less than 6 courses because of ongoing cytopenias.
In conclusion, FCM-R is an active induction regimen for symptomatic patients with CLL. However, clinical response rates and frequency of pts with flow cytometry response < 1% CD5/CD19+ cells does not appear to be different from the FCR experience. Neutropenia occurs in most patients and continued use of hematopoietic growth factors throughout therapy is recommended.
We discussed above the role of therapy in initiating secondary lymphomas in CLL patients, data analysis courtesy of the Mayo Clinic. Below is an equally compelling and detailed analysis of a large database of CLL patients from M. D. Anderson. This one looks at the larger picture of all secondary cancers, not just lymphoid cancers. It is an impressively large cohort of over two thousand patients, and therefore the statistics are likely to be robust. Here are the highlights.
I suppose these results are not all that surprising when you think about it, even though they are startling when seen in such detail. CLL leaves our immune systems unable to cope with a lot of stuff that healthy immune systems can deal with easily. Infections and second cancers are among the major risk factors for people with weak immune systems. The high incidence of skin cancer as a second cancer is not surprising either, and I hope you have already come up the learning curve on this one. If not, I suggest a prompt effort to do so. Here are a couple of Topics articles for your reading pleasure: Dying to Get a Tan?; Vitamin D3: Essential for Health.
One last point to remember as you make your therapy choices: if you are already prone to secondary cancers (most likely skin cancer), or at risk of viral reactivations (as in EBV, with history of prior mononucleosis; see EBV: the Enemy Within) be aware that immune suppressive therapies will make you extra vulnerable. Among the drugs that are known to cause T-cell depletion (T-cells are the major component of our immune system that fight cancer and viral infections) are fludarabine, Campath and steroids. Dr. Terry Hamblin puts it succinctly: after full strength therapy with one or more of these agents your T-cell levels are at the levels seen in full blown AIDS patients. I fully understand and appreciate that sometimes we face rock-and-a-hard-place type of scenarios, when there are no good choices and we have to chose between a bad and worse option. Be forewarned, make sure your local guy is up the curve on all the latest best practices in terms of prophylactic medications and just do the best you can. No one can expect you to do more. Here are a couple of "best practices" articles that may help: Infectious Complications in CLL; Who Is Most at Risk?
2790] Other Malignancies in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Analysis of 2083 Patients.
Session Type: Poster Session, Board #19-III
Apostolia-Maria Tsimberidou, Susan O'Brien, Peter McLaughlin, Sijin Wen, William Wierda, Hagop M. Kantarjian, John Manning, Susan Lerner, Mark Hess, Emil J. Freireich, Michael J. Keating Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; Lymphoma; Biostatistics; Hematopathology
Introduction: Other malignancies are reported to occur with increased frequency in patients with CLL/SLL because of disease- or therapy-related immunosuppression. The purpose of this study was to assess the frequency of other cancers in CLL/SLL patients and to compare presenting characteristics and clinical outcomes between CLL/SLL patients with and without other malignancies.
Patients and methods: We reviewed the records of patients diagnosed with CLL/SLL at The University of Texas M. D. Anderson Cancer Center from 1985 to 2005.
Results: Among 2189 consecutive patients with CLL/SLL, 2083 were evaluable and 572 (27.5%) had another cancer: 39.5% of patients were diagnosed with another cancer before CLL/SLL, 52% after CLL/SLL, 5% prior to and after CLL/SLL, and 3.5% simultaneously with CLL/SLL. Overall, 642 cancers were reported, including skin (30%), prostate (13%), and breast cancers (9%), melanoma (8%), lymphoma (8%), gastrointestinal (7%), lung (7%), urinary tract (5%), genital (4%) and myeloid tumors (2%), head and neck (2%), endocrine (2%), and brain cancer (1%), sarcoma (1%), and other cancers (1%). The median number of other cancers was 1 (range, 1-4). The median time to other cancers after CLL diagnosis was 3.4 years (range, 0-33 yrs). Other cancers were more common in patients with older age (p<0.0001), higher serum 2-microglobulin (p<0.0001) or creatinine levels (p=0.002), male gender (p=0.02), smoking history (p=0.02), lower albumin (p=0.02) or hemoglobin levels (p=0.04), 17p, 6q, or 11q deletion (p=0.03), and longer follow-up (p<0.0001). The median follow-up was 6.2 yrs. Overall survival was shorter in CLL/SLL patients with other cancers compared with those without cancer (median, 10.1 yrs vs. 15.5 yrs; p<0.0001). In treated patients with CLL, patients with other cancers had lower rates of response (59% vs. 65%, respectively; p =0.049), failure-free survival (median, 2.7 yrs vs. 3.5 yrs, respectively; p=0.002), and survival (median, 9.8 yrs vs. 13.1 yrs, respectively; p < 0.0001) compared with those without other cancers. Other malignancies were noted in 303 (28.3%) of 1069 patients who required therapy for CLL/SLL (median follow-up, 7.7 yrs [range, 0.1-33 yrs]) and in 268 (26.4%) of 1014 patients who did not require therapy (median follow-up, 4.7 yrs [range, 0-31 yrs]) (p= 0.35).
The ratio of secondary malignancies/treated patients by therapy was as follows: fludarabine (F)+/-prednisone, 44/173 (25%; median follow-up, 15.9 yrs); F+cyclophosphamide (C), 23/119 (19%; median follow-up, 10.8 yrs); F+mitoxantrone (M), 9/53 (17%; median follow-up, 12.5 yrs); FC+rituximab (R)/FCMR/FMR+dexamethasone (D), 54/492 (11%; median follow-up, 5.9 yrs); R+/-GM-CSF, 6/132 (5%; median follow-up, 1.5 yrs), other therapies, 18/100 (18%; median follow-up, 8.3 yrs).
Conclusions: Other cancers were noted in 27.5% of patients with CLL/SLL. Treated patients had similar rates of other cancers compared to untreated patients (p= 0.35). Other malignancies increased proportionally with time of follow-up and they were associated with inferior outcomes in patients who required therapy for CLL/SLL.
Abstract #2790 appears in Blood, Volume 108, issue 11, November 16, 2006
This is a clinical trial that we reviewed on our website when it was first announced at the Mayo Clinic (Rituxan plus Short Duration Campath) and therefore we were very interested in how it was working thus far.
To recap, this trial looked at combination of Rituxan and short duration Campath (aka “alemtuzumab”) in previously untreated but high risk patients, defined by poor FISH (11q deletion or 17p deletion), or unmutated IgVH gene and positive ZAP70 and CD38. The idea is that these tough luck cases are more likely to progress soon and it might be beneficial to treat them sooner rather than later, especially if the therapy of choice is relatively less toxic monoclonal antibodies rather than conventional chemotherapy. Rituxan as a single agent does not do a whole heck of a lot in poor prognosis CLL patients, and it is hoped that addition of Campath for a short duration will improve things substantially. As most of you know, Campath is one of the few drugs available to us right now that works independent of the 17p (p53) pathway.
This is an interim report, based on 11 patients recruited thus far. No question, there is risk of CMV reactivation with Campath therapy, and it was observed in this trial as well. The patients received anti-virals to protect them against herpes virus (think shingles!), and were continuously monitored for CMV DNA in their blood. The take home lesson is this: Campath therapy requires careful monitoring and protection of patients against viral reactivation. If you opt for getting Campath-based therapies outside of clinical trials, be sure that your local guy follows all of the best practices in this regard.
Very often researchers present response statistics immediately after completion of therapy. We are told there are so many CRs, and so many of them were of the much desired PCR negative variety. (A PCR negative response means there were no CLL cells detected even when blood was tested using our most sensitive methods. Another name for this MRD negative, or negative for Minimum Residual Disease). I have often wondered how these lucky MRD negative folks made out in the long term. Will they stay MRD negative for years and years, “cured” of their CLL for all practical purposes or is this just a more deep remission and like all remissions will it too eventually fail and the patients relapse? Few clinical trials take the trouble of doing sequential MRD testing, looking to see how long the MRD negativity lasts. I am happy to report this extremely well designed study took the extra trouble.
All of the 11 patients analyzed thus far have responded to the therapy. There were 5 out of 11 Complete Responses (CRs), and four of these five were also MRD negative. This is the good news. The not so encouraging news is that each and every one of the MRD negative patients became MRD positive over time, over a period of months. Mind you, these four guys are still in official CR, but the upward trend in their ALC counts suggests that over time these patients too will relapse, eventually. An MRD negative response is not a “cure”, in the English sense of the world but nevertheless such a deep response is likely to give longer lasting remissions. If you want to see the actual charts of these patients, click on the attached presentation in pdf form, which also contains Dr. Zent's analysis of the trial's interim results, written specifically for Topics readers: Presentation on Interim Results.
No question about it, this patient cohort was selected based on their poor prognosis. It is gratifying that all the patients responded but the hematological adverse effects were not trivial and there was no escape from CMV viral reactivation. The researchers’ summation of their results thus far is succinct and honest: “This promising treatment requires further improvement”. We will be following the progress of this trial as more patients are enrolled over time, see how it shakes out over time with larger sample size.
 Alemtuzumab and Rituximab for Therapy of Patents with Early Stage High Risk CLL: Report of a Planned Interim Analysis. Session Type: Poster Session, Board #58-III
Clive S. Zent, Nancy D. Bone, Timothy G. Call, Tait D. Shanafelt, Susan M. Geyer, Charla R. Secreto, Diane F. Jelinek, Gordon W. Dewald, Neil E. Kay Hematology, Mayo Clinic College of Medicine, Rochester, MN
The standard of care for CLL is to treat only patients with obvious clinical progression because earlier intervention is not of proven benefit. The discovery of more accurate prognostic markers for CLL could change that paradigm. The predictors of more aggressive disease include 17p13 deletion (17p13-), 11q22-3 deletion (11q22-), unmutated (UM) immunoglobulin heavy-chain variable region (IgVH), and expression of ZAP-70 and CD38. In addition, monoclonal antibody (MoAb) therapies provide effective treatment with less toxicity than chemotherapy and are likely to be most efficacious in early stage CLL. The combination of alemtuzumab (ALEM) and rituximab (RIT) is of interest because of non-overlapping mechanisms of action. ALEM is also effective therapy for patients with defects in the p53 apoptotic pathway that are more resistance to purine analogue therapy. We tested the hypothesis that MoAb therapy with ALEM and RIT will eliminate/greatly decrease the high risk clone characterized by 17p13-, 11q22-, or UM IgVH plus either ZAP70+ or CD38+, in early stage CLL.
Methods This trial will enroll a maximum of 30 patients and be considered promising if 19 patients respond. All patients with previously untreated CLL (Rai stage 0 II) not meeting NCI-WG 1996 treatment criteria and with a high risk CLL clone were evaluated for enrollment. Treatment duration was 30 days (subcutaneous ALEM dose escalation, 3 mg - 10 mg - 30 mg on days 1-3) then 30 mg Monday, Wednesday and Friday for 4 weeks. RIT (375 mg/m2/dose IV x 4) was administered weekly staring on day 8. All patients received PCP and herpes virus prophylaxis and had CMV viral DNA testing for 7 months. Response was evaluated using NCI-WG 1996 criteria and minimal residual disease (MRD) was measured in peripheral blood using sensitive flow cytometry (1:104) for CD19+/CD5+/CD79b- lymphocytes.
Results Since January 2005, 17 patients have been enrolled and the interim analyses are for the first 11 patients accrued. Median age was 62 years (29 75) with 6 males and 5 females. The qualifying high risk features were 17p13- (n = 4), 11q22- (n = 3), and UM IgVH + CD38+ +/- ZAP-70+ (n = 4). Median time from diagnosis to treatment was 11 months (2-72). Clinical stage (Rai) was 0 in 3 patients, I in 5 patients and II in 3 patients. Median absolute lymphocyte count was 25.6 x 109/L (15.9 81.8), Hgb 14.4 g/dL (12 15.8), and platelet count 171 x 109/L (125 312). Two patients had serious adverse reactions requiring intervention (CMV reactivation responsive to treatment; febrile drug reaction to sulfamethoxazole/trimethoprim). Grade 3-4 adverse reactions not requiring interventions were leukopenia (n = 4), neutropenia (n = 2), anemia (n = 1), elevated ALT (n = 1), and skin reaction to ALEM (n =1). There were no first dose reactions. All patients responded to therapy with 5 CR (4 of these MRD negative), 3 nodular PR, and 3 PR. Median duration of response has not yet been reached at median follow up of 11.7 months (6.5 14.9). Patients with a MRD negative CR had recurrence of detectable MRD at 120 210 days after completing therapy but all remain in CR. One patient died off study of complications of a myeloablative allogeneic transplant for progressive CLL.
Discussion ALEM and RIT is effective and tolerable therapy for early stage high risk CLL. All patients responded with 36% achieving a MRD negative CR but serial MRD assays showed that the CLL clone was not deleted. This promising treatment requires further improvement.
Abstract #2829 appears in Blood, Volume 108, issue 11, November 16, 2006
I am willing to bet some of you have seen the television ad for etanercept (trade name: Enbrel) for treating “the heart-break of psoriasis”. The ad shows how peoples’ lives are dramatically improved, how laughter and love and happiness blooms once the pesky psoriasis is under control. Further along in the ad, there is a very quick and a whole octave lower recitation of the possible side effects, among them the risk of fatal infections such as TB reactivation, cancers such as lymphomas and other fun things. I would not blame you if you did not get this fine print bit, so here is a link to the etanercept website where you can read them at leisure: Enbrel.com.
Why am I talking about psoriasis drugs to CLL patients? Read on. The cytokine that drives psoriasis (and other inflammatory diseases such as Crohn’s disease, ulcerative colitis, etc.) is called TNF-alpha (Tumor Necrosis Factor Alpha, or TNF-α). This inflammatory and anti-cell death cytokine is also involved in driving proliferation of CLL. Prior research at M. D. Anderson and other places has shown that TNF-alpha levels are high in progressive and late stage CLL, and it is thought to protect cancer cells from well deserved death. So, the question is this: will blocking TNF-alpha by using etanercept improve response to Rituxan therapy? Somewhat similar logic goes into the use of anti-inflammatory drugs such as steroids (prednisone), to take away the proliferative underpinnings of the CLL, while Rituxan goes after the cancer cells. I am willing to bet the risk factors of suppression of TNF-alpha in this CLL therapy context are not all that different from the ones identified by the company in the use of etanercept for psoriasis.
Thirty six previously treated patients volunteered for this trial at Ohio State. Etanercept was given as sub-q injections twice a week, 25 mg each time, for 5 weeks. Rituxan was given thrice weekly for 4 weeks, at 375 mg/m2. As one of my friends puts it, these were certainly “manly doses” of both drugs. Twelve out of the 36 patients developed Grade-4 neutropenia (ouch!), and there were somewhat more infections and the like than I would expect from straight Rituxan therapy.
One of the major reasons for doing this clinical trial is that the Ohio State group had seen no responses in their previous work to single agent high dose Rituxan therapy (thrice weekly for 4 weeks) in patients with the dreaded 17p (p53) deletion. The hope was that with the addition of etanercept to the high dose Rituxan, this barrier would be removed. The CLL patients hardest to treat are those with 17p deletions — and yet most of us end up in that place, willy nilly, either as a result of "normal" clonal evolution or helped along by mutagenic and aggressive therapies that select for that scary clone. There was a great deal of emphasis at the 2006 ASH on finding new therapy options for this poor prognostic subset of CLL patients, and this trial was one of them.
Did the etanercept do what it was supposed to do, increase the response rate to Rituxan in poor prognosis patients? I am sorry to report, there was no joy to be had on that front. None of the 8 patients with 17p deletions responded. Moral of the story — if you have 17p deletion, don’t kid yourself into thinking you will get a good and deep response to single-agent Rituxan — no matter how much of it you mainline into your body — and it is not likely that you will improve matters much by the addition of adjuvants such as etanercept.
Once again and for the record, I applaud researchers such as these, who are prompt in publication of their results, honestly and with no spin, whether they be good, bad or indifferent. Brave patients who participate in early phase trials such as this and honest researchers who call it like they see it, are the very basis of any hope we have for better therapies tomorrow.
This is not always the case. I have looked long and hard to see if there was any presentation about the Rituxan + HDMP (high dose methylprednisolone, aka high dose steroids) combination, with or without a Campath chaser to control residual disease after the R + HDMP. This, too, is a drug combination that addresses similar issues: the HDMP and Campath chaser are thought to help with high risk 17p-deleted cases. However, I understand the subject R + HDMP + Campath trial recruits previously untreated and not always 17p-deleted patients. I must admit I do not see the logic for such inclusion criteria.
I have noticed that the R + HDMP + Campath chaser is discussed on many patient chat rooms on the Internet, some of them publishing glowing testimonials from patients who have been through the process. This combination has been around for more than a few years now. So, where are the publications? Where are the peer-reviewed articles in prestigious journals? Why do we still have to make therapy decisions on this front based on nothing more than anecdotal stories or old meeting abstracts? How about the patients that are asking their local oncologists to follow the "UCSD protocol" outside of the actual clinical trial? How much of a safety net do these folks have in the absence of published results?
I have written about this before, and I will keep repeating this until we get some action: Researchers who use human subjects in clinical trials have a fundamental moral and ethical obligation to publish the results of their studies, promptly and fully, and allow their results to be subjected to the scrutiny of their peers. This is at the heart of the Helsinki Declaration adopted by the World Medical Association in 1964 and signed by all civilized countries. No one, and I mean no one, should be exempt from this obligation of full disclosure.
 A Phase II Study of the TNF- Inhibitor Etanercept and Thrice Weekly Rituximab in Relapsed CLL/SLL: Clinical Activity in the Absence of Del(17p13) Genomic Abnormalities. Session Type: Poster Session, Board #70-III
Thomas S. Lin, Margaret S. Lucas, Nyla A. Heerema, Jennifer J. Matkovich, Mollie E. Moran, Carolyn Cheney, David M. Lucas, Donn C. Young, Michael A. Caligiuri, Michael R. Grever, John C. Byrd Division of Hematology and Oncology, The Ohio State University, Columbus, OH; Department of Pathology, The Ohio State University, Columbus, OH
Background: The monoclonal anti-CD20 antibody rituximab induces the death of chronic lymphocytic leukemia (CLL) in part through apoptosis. Tumor necrosis factor (TNF)- and other cytokines up-regulate bcl-2 and other anti-apoptotic proteins, thereby inhibiting apoptosis. In addition, TNF- may play a role in the cytokine release syndrome and infusion toxicity associated with monoclonal antibody therapy. Therefore, antagonists of TNF- represent potential therapeutic agents that may decrease infusion toxicity and enhance rituximab-induced apoptosis.
Methods: We conducted a phase II trial of the TNF- inhibitor etanercept in combination with rituximab in patients (pts) with relapsed CLL or small lymphocytic lymphoma (SLL), to determine if inhibition of TNF- by etanercept increases the clinical activity of rituximab and reduces infusion toxicity. Pts received etanercept, 25 mg subcutaneously (SC) twice weekly during weeks 1-5, and rituximab, 375 mg/m2 intravenously (IV) three times weekly during weeks 2-5. Stepped up dosing was utilized with the first two rituximab treatments.
Results: Thirty-six pts (25 male) with a median of 2 prior therapies (range 1-8) were enrolled; 23 pts had previously received rituximab. Therapy was generally well tolerated. Infusion reactions were mild and were not associated with severe adverse events. Fourteen pts experienced grade 1 (n=5) or grade 2 (n=9) infusion reactions. These infusion reactions extinguished with subsequent does of rituximab. Twelve pts developed grade 4 neutropenia, and neutropenic infections occurred in 4 pts, with 3 of these infections occurring during rapid CLL progression. Twelve pts developed grade 2 (n=10) or grade 3 (n=2) non-neutropenic infections. Nine of 32 evaluable pts (28%) achieved an NCI 96 response, with 8 partial responses (PR) and 1 complete response (CR). Median duration of response was 10 months. Eighteen pts had stable disease (SD), while 5 pts had progressive disease (PD). No responses were observed in 8 pts with del(17p13). In contrast, 9 of 24 pts (38%) without del(17p13) responded, including 3 pts with complex karyotypes. Sixteen pts with responsive or stable disease did not require additional treatment for CLL for 6 months after end of therapy, and the median treatment free survival for this group was 12 months. Eight of these 16 pts have not yet required other CLL therapy.
Conclusions: This study confirms our previous finding that single agent thrice weekly rituximab is ineffective in relapsed CLL with del(17p13) (Cancer Res 63: 36, 2003). The combination of rituximab and etanercept was well tolerated and demonstrated clinical activity in relapsed CLL pts without del(17p13). However, the addition of etanercept did not improve the clinical response rate beyond that expected with single agent thrice weekly rituximab.
Abstract #2841 appears in Blood, Volume 108, issue 11, November 16, 2006
Lets face it. Those of us with proliferative CLL will eventually need therapy for it, and each relapse requires ever more aggressive therapy regimens. It is a slippery slope my friends. As the slope becomes steeper, we find ourselves with more and more chromosomal abnormalities, brought on by the unstable nature of the CLL itself (think unmutated IgVH genes) or the mutagenicity of the therapies used to control it. Complex karyotypes with multiple cytogenetic defects and high risk abnormalities such as a 11q (ATM) deletion or a 17p (p53) deletion make it much harder to get deep or long lasting remissions. You may have a perfectly matched stem cell donor all lined up but how are you to going to initiate the potentially curative mini-allo transplant (The Only Real Cure) if you cannot first get a decent remission going into the transplant? Remember, success rates for mini-allos are much higher for patients who go into the transplant with no more than bare minimum residual disease left over. It is not a good idea to leave the heavy lifting to the newly grafted immune system, that job should be taken care of ahead of time.
There was a palpable sense of urgency on this front at this year’s ASH conference. I think the era of prognostic indicators (FISH, IgVH gene mutation status, etc.) is finally taking hold, and the implications are inexorable. We need new therapies that do a better job of dealing with poor prognostic patients, especially those with 17p (p53) deletions. Right now, only three drugs have shown efficacy in dealing with CLL cells that have lost the p53 gene: Campath, Flavopiridol and high dose steroids. None of them is a walk in the park. Dr. Andrew Pettitt rightly calls Campath + high dose steroids a “sledgehammer to be used wisely”. I made sure that my very busy itinerary at ASH allowed me to attend the Ohio State University oral presentation on the third agent in the line up, namely flavopiridol. Here are links to our previous articles on this drug, if you want to get some of the background information: 17AAG, Flavopiridol: A Drug that May Save Lives.
Earlier clinical trials using flavopiridol were frustrating. Its remarkable ability to kill CLL cells in the lab did not track when the drug was used in human patients, the cancer cell kill was less than wonderful. It took good science and pharmacokinetic sleuthing to find out what was happening. It turns out flavopiridol is bound very strongly to human plasma proteins. As soon as the drug was injected into patients in the early trials, it was all sucked up and taken out of circulation by getting attached to plasma in the blood. Net result, the cancer cells did not even see much of the drug, let alone enough to kill them.
The new drug administration protocols call for a “bolus” (one shot) administration of flavopiridol, enough of it to saturate all of the plasma proteins. Once that is out of the way, more drug is administered as an intravenous infusion over 4 hours. This time there is no way for the drug to get sequestered by being bound to human plasma proteins and therefore a substantial concentration of it builds up in the blood, able and willing to kill CLL cells. This "pharmacological dosing scheme" is the approach used in later trials and they have shown improved responses in patients.
Nothing about flavopiridol is easy. Besides the problem of getting enough of the drug to the CLL cells, the other major concern is the speed and rapidity with which the drug kills cancer cells. Think of it as a feast or famine scenario — there are no nice and comfy half measures with this drug. The very rapid rate of cancer cell kill may trigger something called “Tumor Lysis Syndrome”, TLS for short. TLS can precipitate an avalanche of cytokines and this over-the-top storm can pretty quickly overwhelm the capacity of the liver and kidneys to get rid of the poisons and debris of the dying cells. Better understanding of this phenomenon has led to better control of it, including access to dialysis to protect liver function when necessary.
The good news: flavopiridol works in some of the toughest cases among our patient community, including those with 17p (p53) deletions. We seem to have figured out how to get beyond the problem of the drug getting removed from circulation by virtue of getting sucked up by plasma proteins. The not so good news, Tumor Lysis Syndrome is still a major problem, the single biggest dose limiting toxicity. You can read the full details in the abstract and table given below.
Would it be possible to control this serious adverse effect better in the future, for example by treating patients with low tumor load, at an earlier stage of the proliferative process? Should flavopiridol be used only for MRD clean up, when there is only a small amount of tumor cells to be killed? Would it help to carry out leukapheresis ahead of time, to bring down some of the circulating counts of CLL cells? I do not know if these approaches are likely to help and/or if there are better ways of achieving control over TLS. We can only hope that future clinical trials using flavopiridol will be able to use the remarkable potency of the drug in killing refractory CLL cells, while reducing and controlling some of the toxicities associated with it. For now, flavopiridol continues to be an extremely important and interesting drug and we will continue to monitor its progress in clinical trials.
 Flavopiridol Is Active in Genetically High-Risk, Relapsed Chronic Lymphocytic Leukemia (CLL): Analysis of 56 Patients by Cytogenetic Abnormality. Session Type: Oral Session
Thomas S. Lin, Nyla A. Heerema, Beth Fischer, Kristie A. Blum, Mollie E. Moran, Michelle B. McEldowney, Sara Broering, Gerard Lozanski, Dimitrios Colevas, Michael R. Grever, John C. Byrd Division of Hematology and Oncology, The Ohio State University, Columbus, OH; Department of Pathology, The Ohio State University, Columbus, OH; Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD
Background: Treatment options for relapsed CLL patients (pts) with high-risk genetic features, such as del(17p13) or a complex karyotype, are limited. Flavopiridol induces p53-independent apoptosis in CLL cells in vitro, but increased drug binding to human plasma proteins resulted in lack of clinical activity using 24-72-hr continuous IV infusion (CIVI) schedules. Pharmacokinetic (PK) modeling indicated that administering flavopiridol by IV bolus (IVB) followed by 4-hr CIVI would achieve the necessary concentration to induce apoptosis of CLL cells.
Study Design and Treatment: We conducted a phase I study of this PK-derived dosing schedule in relapsed CLL. Pts received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses, every 6 weeks for up to 6 cycles. Fifty-eight pts (43 male) with relapsed CLL (n=48) or small lympocytic lymphoma (n=10) were enrolled. Median age was 60 years (range, 38-84). Median number of prior therapies was 4 (range, 1-14); 57 pts had received prior fludarabine, with 48 pts refractory to or intolerant of fludarabine. Pts had bulky Rai stage I/II (n=13) or III/IV (n=45) disease. In the initial 2 cohorts, pts received 30 mg/m2 IVB + 30 mg/m2 CIVI (n=20) or 40 mg/m2 IVB + 40 mg/m2 CIVI (n=3). Dose limiting toxicity was acute tumor lysis syndrome (TLS) in 2 pts in cohort 2. Thirty-five pts were enrolled in cohorts 3 and 4, in which flavopiridol was dose escalated to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with cycle 2 (n=14) or dose 2 of cycle 1 (n=14) if severe TLS was not observed. Seven pts experienced severe TLS and did not undergo dose escalation.
Response Assessment: Fifty-two of 58 pts were evaluable for response. Six pts who received only one dose of study drug due to grade 4-5 acute TLS and other complications were not evaluable for response. Twenty-six pts achieved a partial response (PR; 50%) by NCI Working Group response criteria. Median progression free survival (PFS) of all responders is 11 months (range, 5-29), and 10 pts remain in remission. Twenty-one of 39 evaluable pts with bulky adenopathy > 5 cm attained PR (54%). Thirteen of 27 evaluable pts with a complex karyotype achieved PR (48%); median PFS is 10 months (range, 5-16), and 4 pts remain in remission. Nine of 19 evaluable pts with del(17p13), corresponding to loss of the p53 tumor suppressor gene, attained PR (47%); median PFS is 10 months (range, 8-16), and 5 pts remain in remission. Seventeen of 21 evaluable pts with del(11q22), resulting in loss of the ATM tumor suppressor gene, achieved PR (81%); median PFS is 11 months (range, 8-15 months), and 6 pts remain in remission.
Conclusions: Flavopiridol is highly active in heavily pretreated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features such as a complex karyotype or del(17p13). Flavopiridol appears to be particularly active in pts with del(11q22), corresponding to loss of the ATM tumor suppressor gene. The mechanism of action of flavopiridol is under active investigation.
All patients (n=58)
Complex karyotype (n=29)
Deletion of 17p13 (n=20)
Deletion of 11q22 (n=22)
Abstract #302 appears in Blood, Volume 108, issue 11, November 16, 2006
Four new drugs (relatively speaking) were the focus of the buzz in the CLL meetings. We have discussed one of them above, namely flavopiridol. The other three were Celgene's Revlimid (thalidomide analog, generic name lenalidomide), Genta’s Genasense, and Genmab's HuMax-CD20.
I have to admit I have not been a big fan of Revlimid. I felt that the drug had way too much toxicity, and that turned me off. However, talking with several researchers whom I hold in high esteem, I have come to realize there may be more to this drug than meets the eye on a cursory look-see. For that reason, I have decided to do a full length article on the subject of Revlimid. I am waiting to get some additional information from Celgene, the company that makes Revlimid and as soon as I have all the material at hand I will review this new drug. The hallmark of a good scientist is not to get hung up on ego issues. You have to be willing to accept new information when it becomes available. I will do my best to give you a fair and balanced view of Revlimid in the next couple of weeks.
As for Genta’s bcl-2 blocking drug Genasense, I am afraid time has run out for this one. The FDA has just ruled that the drug is not approvable for CLL based on submitted data. The stock price has taken a beating accordingly (down from an all time high of more than $150.00 to a mere $0.50!) and I doubt there is much wiggle room left. Not withstanding positive reports about this drug on some patient websites, I was not particularly surprised by the FDA’s decision. Genasense failed its primary endpoints in the most recent clinical trial. Sure, they saw a benefit in a subset of patients who participated. But that can be considered a case of retrospective slicing and dicing of the statistics. Almost any dataset can be sub-divided to give preferred answers, if only one looks at smaller and smaller subsets. Statisticians take a dim view of this process. That is why drug companies have to state what their primary goals are, ahead of conducting the trial (prospectively, not retrospectively after the trial is over and the data has been collected), and they are judged on whether or not these stated goals are met. Whether you agree with this process or not is somewhat moot now. The FDA has spoken, and I doubt you will be able to get Genasense in the United States as a commercially available drug in the years to come. R.I.P.
Last but not least, there was a buzz about Genmab’s new monoclonal antibody HuMax-CD20. We have several articles on the subject. Sons of Rituxan and Campath; Results from Genmab's HuMax-CD20 Clinical Trial; Genmab in the News; HuMax CD-20 Risks and Rewards. There was speculation of Genmab linking up with one of the big pharmaceutical companies to help market HuMax-CD20 (which has the generic name “ofatumumab”), and sure enough, this week there was a formal press announcement that Genmab has given world wide marketing rights to Glaxo-Smith-Kline (GSK). If you are the financial type, here is the official press release about the Genmab and GSK alliance for HuMax-CD20, and no doubt you will also notice Genmab’s stock price has been climbing nicely for the past year or so. We also met with several of the Genmab people at ASH, and we will be reporting on their latest clinical trial for chemo-naïve CLL patients in the next couple of days.
All in all, your two reporters had an interesting time of it. There were 20,000 or more hematologists from all around the world, the conference was wall-to-wall with expertise, erudition and egos. I think some of these guys are still getting used to the idea of patients listening-in on their conversations. As some of you may remember, ASH was very clear in refusing us admission to their conferences when we tried to register as patients. But as members of the Press, why, that is an entirely different matter! All the registration charges were waived, and we were treated as well as the rest of the ASH press corps: even got free bagels and sandwiches, etc., for breakfast and lunch.
As for the discomfort of some of the researchers about patient oversight, I think they had better get used to it. The drug companies have certainly made the adjustment: a few of them wrote to us ahead of time and set up times when they could meet with PC and me to tell us all about themselves. The day of the Internet is here, as is the reach and influence of patient education and advocacy publications such as CLL Topics. Cozy and exclusive clubs don’t work anymore. We — and others like us — will be there, looking things over, commenting on and comparing clinical trials, giving honor where honor is due and expressing concern when that seems to us the right thing to do. In the long run, I think this helps all parties involved. Let’s face it — we all want the same thing, better and less toxic therapy options for cancer patients. All that has changed is that now patients are active participants in the process of getting there, not just intimidated “victims”. I don’t know about you, but from my viewpoint, it could not have happened soon enough.
Disclaimer: The content of this website is intended for information only and is NOT meant to be medical advice. Please be sure to consult and follow the advice of your doctors on all medical matters.
Copyright © 2002-2007 CLL Topics, Inc. All Rights Reserved.
All materials contained on this site are protected by United States copyright law and may not be reproduced, distributed, transmitted, displayed, published or broadcast without the prior written permission of CLL Topics, Inc. You may not alter or remove any trademark, copyright or other notice from copies of the content.
However, you may download and print material from CLLTopics.org exclusively for your personal, noncommercial use.
Topic: Meetings & Conferences