Date: July 4, 2007
by Chaya Venkat
Most of us who came of age during the 60’s and 70’s or thereabouts have read “Catch 22”, written by Joseph Heller. For you, I don’t have to explain what a “Catch 22” is. For those who are unfortunate and have not read this hilariously funny and unforgettably sad and manic book about bureaucratic operation and reasoning, Catch-22 is a situation where you cannot win for losing, no matter what you do. This article is all about a potential catch-22 faced sometimes by CLL patients cursed with poor prognostics. Here is some mind-numbing logic I found bewildering.
This is a scenario worthy of a Heller novel. Sorry, I am not up to the literary standards of Joseph Heller. But I will do my best to outline the scenario faced by “Richard”, a real patient whose identity has been disguised. As in the case of our other hypothetical patient “Harvey”, the clinical details and therapy discussions are true to life, but the patient’s name has been changed to protect his identity.
Please allow me to introduce “Richard”, a member of CLL Topics and hero of this case study. Richard is 45 years young, a mountain climber, long distance runner, scout master, father of five and devoted husband. Talk about having reasons to want to live: Richard has plenty of them. He is well educated, willing and able to learn and take charge of his own healthcare. Like the hypothetical hero of our Harvey saga, Richard is not one to bury his head in the sand. He knows he is best served when he takes a clear look at the lay of the land, and makes decisions that are right for him and his family.
Richard was diagnosed with CLL in late 2006, pretty much the same way most of us are diagnosed — a routine blood test showed he had elevated WBC, in the range of 40K. The rest of the counts looked OK and he had only mildly swollen lymph nodes. There were no other symptoms.
Prognostic testing revealed CD38 expression was negative (done by an outside commercial lab), but he was positive for ZAP-70 (42%), an indication of potentially aggressive disease. In keeping with this, FISH analysis revealed deletion of 13q as well as the dreaded17p (p53) deletion and IgVH was definitely of the (bad) unmutated variety. Additional work showed an unstable phenotype, with multiple other chromosomal abnormalities that are not even looked for in a run-of-the-mill FISH test. A direct Coombs test was positive, suggesting possible autoimmune complications down the road. A bone marrow biopsy done March of this year showed 100% cellularity, with 80%-85% infiltrated by CLL cells — not much room left there, especially in view of his rapidly multiplying variety of CLL. Bummer!! This guy had pretty much every negative indicator on the charts, solidly in Bucket C on all counts.
A mere couple of months after diagnosis the CLL was already on the march. Richard had mildly swollen spleen, a white cell count doubling time of less than 6 months and a CT scan showed enlarged lymph nodes (around 2.2 cm) in numerous locations. He started having night sweats several times each week, he became a little anemic, his beloved hobby of long distance running became a harder and there was more fatigue. Though, raising five kids and holding down a high pressure job, I don’t know how he had the time or energy to run at the best of times. Our hero is surely made of sterner stuff, no wimp is he. Nevertheless, his poor cytogenetics and the onset of “b-symptoms” (anemia, fatigue, night sweats) staged him as high risk Rai Stage III patient. The only other clinical features from his past were a peptic ulcer 20 years ago and one episode of basal cell carcinoma.
Richard is my kind of take-charge guy, and he did a bit of shopping around before he decided on his first CLL therapy. Keeping his eyes wide open, Richard knew his aggressive CLL was not going to respond to kinder and gentler approaches. He considered Campath (or perhaps the "Sledgehammer" combination of Campath + high dose steroids), but his lymph nodes had already swollen to 3cm and more, making Campath less attractive (Campath is notoriously poor at clearing bulky lymph nodes). Fortunately, he fit the inclusion criteria for the recently announced FC + HuMax-CD20 clinical trial (think of this combination as the HuMax-CD20 version of the FCR combination pioneered at M. D. Anderson). The idea was that as long as FC+HuMax-CD20 seemed to be working, Richard would continue and complete the 6 cycle regimen. After that, Richard would be evaluated for MRD (minimum residual disease) status. There was the possibility of a Campath chaser to get rid of any residual disease, if it became necessary.
As we speak, Richard has finished the first few cycles of FCH and is doing pretty well. His soaring white blood counts have come down, lymph nodes have shrunk nicely and the fatigue has improved. Everything is on track for getting a decent remission but only time will tell if it will be a full CR and even then, it is hard to predict how long the remission will hold. HuMax-CD20 is a new drug which we have written about extensively on this website. We have high hopes for this fully human anti-CD20 monoclonal antibody. But we do not have track record for FCH, yet, and the best Richard can hope to do is extrapolate based on published results for FCR.
Richard’s bet is that he will (hopefully) get a decent remission from the FC + HuMax-CD20 experimental protocol, perhaps even a CR (“complete response”), but chances are slim that the remission would last any great length of time. What to do for an encore? Patients with his prognostic profile rarely get a second remission that is as good as the first one. He is a young man, with a lot of life to live. It was clear to him that an allogeneic stem cell transplant was in his future, sooner or later. It would have to be a MUD (matched unrelated donor) transplant since his siblings did not match. Fortunately, unlike “Harvey”, he is pretty standard issue in terms of ethnicity and even a cursory search revealed dozens of good matches in the donor banks.
Richard is not one to sit idly and let grass grow under his feet. He believes in meticulous planning, being the type that wants to see around the bend and get a handle on what is coming at him down the road. He went shopping once more, this time to get advice regarding the timing and manner of his future mini-allo MUD transplant. He chose three centers of excellence, one each in California, Seattle and Texas. I will summarize for you the assessment and advice he got from each institution, as well as Richard’s decision after listening to all the experts. You can then decide for yourself if you agree with him, if in his shoes you would have made the same call yourself.
Ahh, golden sunshine, pretty girls and the laid-back lifestyle of sunny California. Getting a stem cell transplant in such a lovely location would surely be a lot easier than in less lovely surroundings? This institution has some of the best CLL experts, their specialists rank in the top dozen or so in the whole world. They conduct many clinical trials in CLL and their research publications are the basis for CME (continuing medical education) for local oncologists in this country and elsewhere. These guys were no slouches when it came to CLL expertise: surely they would know exactly what he should do to maximize his chances of dying an old man some day in the distant future? Paraphrased below is what the California experts had to say:
Richard could not have asked for a more complete work-up of his case — and he pretty much agreed with the expert's recommendations. But there was one nagging worry at the back of his mind. This is clearly a CLL expert center. But how much practice did they have in doing stem cell transplants? He knew experience counted for a great deal when one is considering stem cell transplants. These guys knew their CLL, but when it came to the sheer volume of transplants done and experience gained, they were not at the top of the list. Perhaps he had better consult some folks who live and breathe transplant technology for a living, their biggest claim to fame.
Our West Coast city of Seattle is the well known home of software companies, more coffee shops per capita than any place on earth, lots of rain, and the biggest and best-known transplant center in the whole country, perhaps the world. PC and I visited the same institution recently, and we were most impressed by their expertise and professionalism. Did you know, the very first stem cell transplant in humans was done there, back in the 60’s? I give full marks to our hero for making good choices for his fact finding. This is what the Seattle transplant experts had to say:
|Number of Patients||Disease Status
prior to Mini-allo
|% of Patients
Whose CLL Relapsed
|Hutch Risk Category|
|7||Full CR||14 months||None||Low Risk|
|75||Not in Full CR||14 months||31%||Standard Risk|
Biol Blood Marrow Transplant. 2006 Oct;12(10):1056-64
Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia.
Brown JR, Kim HT, Li S, Stephans K, Fisher DC, Cutler C, Ho V, Lee SJ, Milford EL, Ritz J, Antin JH, Soiffer RJ, Gribben JG, Alyea EP. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Although chronic lymphocytic leukemia (CLL) remains an incurable disease with standard chemotherapy, the appropriate role and timing of transplantation are unclear. In this analysis, we report the outcomes of 46 patients with advanced CLL who underwent nonmyeloablative stem cell transplantation (NST) from HLA-matched unrelated (67%) or related (33%) donors. Fludarabine (30 mg/m2 x 4) and low-dose intravenous busulfan (0.8 mg/kg/day x 4) were used for conditioning. The 2-year overall survival (OS) and progression-free survival (PFS) rates in this refractory patient population were 54% and 34%, respectively, with a median follow-up of 20 months. The primary cause of treatment failure was relapse, with a 2-year cumulative incidence of 48%. High hematopoietic donor chimerism > or = 75% at day +30 was a significant predictor of 2-year PFS (47% vs 11%; P = .03). In multivariate analysis, chemotherapy-refractory disease at transplantation was associated with a 3.2-fold risk of progression (P = .01) and a 4.6-fold risk of death (P = .02). Increasing number of previous therapies and increasing bone marrow involvement were also associated with decreased PFS and OS. These results suggest that NST using fludarabine and low-dose intravenous busulfan is a reasonable treatment option for patients with advanced CLL, but that NST earlier in the disease course will likely be needed to achieve long-term disease control in a high proportion of patients.
Same patient, two different expert centers with different areas of expertise, two very different recommendations. California had CLL expertise in buckets, but they have not done all that many mini-allo transplants. Were they under-estimating the real risks involved in a stem cell transplant, even the reduced intensity (non-myeloablative, “mini-allo”) variety? Were they jumping the gun, being overly influenced by their detailed awareness of the latest molecular prognostics and their understanding of how these poor prognostic indicators are likely to effect Richard’s response to conventional therapy and not paying enough attention to the risks and horrors of a stem cell transplant?
Seattle has done more stem cell transplants than any one else, but perhaps they do not distinguish all that much between the various lymphomas and leukemias, let alone worry about the fine distinctions between the various risk buckets in CLL, at least as an institution. Perhaps their guidance was being influenced by the grim survival statistics associated with transplanting aggressive myeloid cancers and the like, their typical case load most of the time? Could it be that they were still stuck in the conventional wisdom of yesterday, that CLL is the “good cancer” to have and the only time to transplant CLL patients is as a “hail-Mary” salvage attempt when all other options have failed? Surely the concept of risk-stratified therapy choices for CLL patients has now obtained sufficient credibility? Mind you, I am impressed that in their efforts to protect the patient from harm, these guys are turning away paying customers. Mini-allo transplants are not cheap, insurance companies get billed a cool half million dollars (or more, for complex cases) for each patient they transplant. Whatever else is happening here, greed at the expense of patients is definitely not the issue.
After spending a couple of sleepless nights in Seattle, Richard headed out to Texas, to see if he could find a tie-breaker.
The expert center Richard visited next is truly Texas-style, larger than life in every way. CLL experts? They have more world class experts than you can shake a stick at. Transplant expertise? These guys take exception to the commonly held opinion that the Seattle center does more transplants. No sir, Texas takes second place to no one. Definitely, they have done more mini-allo transplants for CLL patients. Perhaps this was the expert center for our hero, the “Goldilocks perfect scenario” of CLL expertise and transplant expertise, present in one institution. Richard is all too familiar with the roadblocks of “not invented here” syndrome that creates impenetrable silos even in our best and brightest institutions. Perhaps the fact that both sets of expertise resided in the same institution meant there was less chance of “silo” mentality. This is the advice Richard got from Texas:
I will end the suspense right here. Richard voted with his feet, he chose the transplant center that best reflected his own well-informed preference. He will meet his new immune system in Texas. He will go ahead with his game plan of a mini-allo MUD transplant, at the Texas transplant center, as soon as he is done with his FC + HuMax-CD20 therapy. He has chosen to proceed with his “elective” transplant, rather than wait to get a “rescue” or “salvage” transplant some time in the future. He is happy he chose to visit all three centers, he learned a great deal from all the experts he met. In each case, he respected their sincerity and expertise but in the final analysis he felt the Texas center suited his preferences the best. He prefers to take his chances with a successful mini-allo sooner, rather than risk an out-of-control CLL that complicates transplanting later on. We wish him good luck, and we look forward to publishing his updates.
Each expert that Richard consulted felt he knew exactly what Richard should do. We can only hope that in the near future the divergent opinions expressed by the experts in each center will gradually come together into a set of “Best Practices”, clear guidance to patients and their families. Right now, it is pretty much a case of patients voting with their feet, picking a transplant center that agrees with the patient’s preferred game plan. It is a stressful process to say the least, when it comes to life-and-death decisions such as this.
Where in all this did the patient’s personal preference figure? How much of a role should an informed and articulate patient have in making these life and death decisions? If it is OK for patients to volunteer for significantly more risky “blue-sky” exploratory clinical trials because they have given their “informed consent”, how about similar courtesy for informed patients like Richard making the therapy choices that are right for them, after weighing all the pros and cons, after listening respectfully to all the experts? Where does concern for patient safety end, and where does respect for patient’s freedom to choose begin? After all, whose personal risk is it anyway?
Along the same lines, what is the value given to the guidance provided by the CLL physician referring the patient to the transplant center? In Richard’s case, his expert hematologist had very clear guidance for him: he had better not waste the window of opportunity offered by his first (hopefully) good remission, he had better get a mini-allo transplant right away. This guidance was overruled by the institutional guidelines of the Seattle transplant center. Should there have been more of a discussion between Seattle and Richard’s CLL expert? Should Seattle have paid more attention to the considered opinion of an expert who had seen far more "Bucket C" CLL cases than Seattle ever did, and had a better understanding of the implications of poor prognostics? Is this yet another example of silo mentality, where experts from different fields do not consult sufficiently to reach a consensus?
As I look at the CLL landscape, I see few if any breakthrough drugs in the pipeline that offer the potential of actually curing this incurable cancer in the near future, most likely not soon enough to be of personal value to us chickens with this nasty disease, right now. More of us will be considering stem cell transplants than ever before, rightly so, since the development of “mini-allo” transplants have taken a big bite out of the risks associated with this procedure and incidentally, made them available to older patients. The risks-versus-rewards balance of a mini-allo transplant are gradually tilting in favor of the rewards for more patients, especially patients with poor prognoses who choose to take responsibility and make decisions.
How do we fight insurance companies that refuse coverage for this very expensive procedure, when institutional guidelines such as those at Seattle give them fig-leaf excuse that CLL patients should only be transplanted if they are in very late Rai stage disease? I am not making this up folks. This has happened in a real case just a short while ago: a real patient has been denied coverage for a transplant, because he/she was not sufficiently far gone, never mind the patient’s physician (one of the most highly regarded CLL experts) felt an immediate transplant was in the best interest of his patient.
We will be conducting what would be a new experiment for CLL Topics. With the explicit permission of our hypothetical hero Richard, we will bring his very real case to the attention of CLL experts and transplant experts, ask for their comments. I do not know how many of them will respond, and if any of them will be willing to go on the record. If any of them give us permission to publish their comments, we will thank them sincerely for that act of leadership, and publish their comments on our website.
Prognosis at Diagnosis and Risk-adapted Therapy Choices are phrases we have been hearing for years now, from some of the best CLL experts. It is time we got our best brains together, CLL experts and transplant experts, and define consensus guidelines that help patients avoid the “Catch-22” no-win situation many of us face right now. Europe has already taken the lead on this important issue, taking a stab at risk-stratified transplant decisions (see the first abstract below). Stay tuned folks. This is an important and complex area. It is time we got a real dialogue going on this important subject between CLL experts, transplant experts, patients, and yes, even insurance companies. Our lives depend on it.
Leukemia. 2007 Jan;21(1):12-7.
Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.
Dreger P, Corradini P, Kimby E, Michallet M, Milligan D, Schetelig J, Wiktor-Jedrzejczak W, Niederwieser D, Hallek M, Montserrat E
Chronic Leukemia Working Party of the EBMT.
Department of Medicine V, University of Heidelberg, Heidelberg, Germany
The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-SCT) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MEDLINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus are (1) allo-SCT is a procedure with evidence-based efficacy in poor-risk CLL; (2) although definition of 'poor-risk CLL' requires further investigation, allo-SCT is a reasonable treatment option for younger patients with (i) non-response or early relapse (within 12 months) after purine analogues, (ii) relapse within 24 months after having achieved a response with purine-analogue-based combination therapy or autologous transplantation, and (iii) patients with p53 abnormalities requiring treatment; and (3) optimum transplant strategies may vary according to distinct clinical situations and should be defined in prospective trials. This is the first attempt to define standard indications for allo-SCT in CLL. Nevertheless, whenever possible, allo-SCT should be performed within disease-specific prospective clinical protocols in order to continuously refine transplant indications according to new developments in risk assessment and treatment of CLL.
Article from Clinical Cancer Research (full-text PDF)
Clin Cancer Res. 2005 Nov 1;11(21):7757-63.
Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-).
Caballero D, García-Marco JA, Martino R, Mateos V, Ribera JM, Sarrá J, León A, Sanz G, de la Serna J, Cabrera R, González M, Sierra J, San Miguel J.
Hospital Clínico Universitario de Salamanca, Spain.
PURPOSE: To evaluate the efficacy of reduced intensity conditioning (RIC) allogeneic transplant in 30 patients with poor-prognosis chronic lymphocytic leukemia (CLL) and/or high-risk molecular/cytogenetic characteristics.
EXPERIMENTAL DESIGN: Eighty-three percent of patients had active disease at the moment of transplant. That is, 14 of the 23 patients analyzed (60%) had unmutated immunoglobulin variable heavy-chain gene (IgV(H)) status; 8 of 25 patients (32%) had 11q-, with four of them also displaying unmutated IgV(H); and six (24%) had 17p- (five were also unmutated).
RESULTS: After a median follow-up of 47.3 months, all 22 patients alive are disease free; overall survival and event-free survival (EFS) at 6 years were 70% and 72%, respectively. According to molecular/cytogenetic characteristics, overall survival and EFS for unmutated CLL and/or with 11q- aberration (n = 13) were 90% and 92%, respectively, not significantly different to those with normal in situ hybridization, 13q- and +12, or mutated CLL (n = 7). All six patients with 17p deletion were transplanted with active disease, including three with refractory disease; all except one reached complete remission after the transplant and two are alive and disease free. Nonrelapse mortality (NRM) was 20%; more than two lines before transplant is an independent prognostic factor for NRM (P = 0,02), EFS (P = 0.02), and overall survival (P = 0.01). Patients older than 55 years have a higher risk of NRM (hazard ratio, 12.8; 95% confidence interval, 1.5-111). Minimal residual disease was monitored by multiparametric flow cytometry in 21 patients. Clearance of CD79/CD5/CD19/CD23 cells in bone marrow was achieved in 68% and 94% of the patients at days 100 and 360, respectively.
CONCLUSION: According to these results, RIC allogeneic transplant could overcome the adverse prognosis of patients with unmutated CLL as well as those with 11q- or 17p-.
Article from Journal of Clinical Oncology (full-text PDF)
J Clin Oncol. 2006 Jan 20;24(3):437-43. Epub 2005 Dec 12.
Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy.
Byrd JC, Gribben JG, Peterson BL, Grever MR, Lozanski G, Lucas DM, Lampson B, Larson RA, Caligiuri MA, Heerema NA.
Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
PURPOSE: Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig V(H) mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy.
METHODS: We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712.
RESULTS: Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig V(H) mutational status to classify risk, there was no association between complete response rate with either unmutated Ig V(H) mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig V(H) unmutated patients as compared with the Ig V(H) mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk.
CONCLUSION: These data demonstrate that high-risk CLL patients characterized by Ig V(H) unmutated (> or = 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig V(H) mutational status and interphase cytogenetics on treatment outcome.
Blood. 2007 Jun 26; [Epub ahead of print]
Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.
Kahl C, Storer BE, Sandmaier BM, Mielcarek M, Maris MB, Blume KG, Niederwieser D, Chauncey TR, Forman SJ, Agura E, Leis JF, Bruno B, Langston A, Pulsipher MA, McSweeney PA, Wade JC, Epner E, Petersen FB, Bethge WA, Maloney DG, Storb R.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55; range, 5-74 years) received related (n=498) or unrelated (n=336) HCT after 2 Gy total body irradiation alone (n=171), or combined with fludarabine (90 mg/m(2); n=663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing non-relapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with CLL and MM in remission (CR), low-grade or mantle cell NHL (CR + PR), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of >0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.
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