Date: August 17, 2005
by Chaya Venkat
Editor's Note: This article is based on a teaching case study titled "Clinical Reasoning in Oncology" published in the July/August 1999 issue of Cancer Control, the peer-reviewed journal of the H. Lee Moffitt Cancer Center & Research Institute, in Tampa FL. The journal is sent at no charge to 13,000 professionals including oncologists in all sub-specialties. It is indexed in MEDLINE. This case history and the expert comments represented state-of-the-art information back then. But the advanced thinking of a few years ago has become the outmoded conventional thinking of today. Periods of rapid change can be frustrating and dangerous, especially when professionals do not keep up with the great volume of new research literature in the field. The divergence between the original case analysis and Chaya's critique demonstrate how patients can find themselves caught in the "death by conventional wisdom" syndrome if their oncology/hematology professionals have not kept up.
Doctors don’t always share with us their logic and reasoning for their recommendations. Let’s face it, there is only so much that can be achieved in a 15 minute interview. Doctors feel (often correctly) that the jargon is intimidating to patients. Many doctors also seem to feel that therapy decisions are best left to the experts — an attitude best summed up by the words, "don’t you worry your pretty little head about it."
Below is a truly fascinating case history of a CLL patient back in 1999, the bad old days before monoclonal antibodies came on the scene. I could not have made up this case history in my most pessimistic mood. This case describes the poor patient's slide from the point of diagnosis through ineffective chemotherapy to bone marrow transplant and death — all in about a year and half. The expert consultant recommendations were by the book, the state of the art back then. The same recommendations would be seriously out-of-date today. The scary thing is how many local oncologists still play by this outdated playbook. The good news is that if one is smart about it, many of the pitfalls of back then can be avoided today. We can do a lot better than the grim survival statistics quoted for CLL patients before Rituxan and Campath came on the scene. It goes without saying, you cannot get the benefits of the new think if you are using a 1999 playbook!
I have no formal medical training, none, zip, nada. My understanding of CLL is no more than that of an interested layperson observer. But I think you will get a kick out of reading my decidedly non-expert comments interspersed in this case history. My comments are in blue, so you don’t confuse them with the text of the original article and the expert consultant’s comments, which are in black. I call the unfortunate results of this case study, “Death by Conventional Wisdom”.
From the Blood and Marrow Transplant Program at the H. Lee Moffitt Cancer Center & Research Institute at the University of South Florida, Tampa, Fla (BD), the Department of Medicine and Division of Medical Oncology/Hematology at the University of Louisville James Graham Brown Cancer Center and Louisville VA Medical Center, Louisville, Ky (FJH), and the Section of Oncology and Hematology at the Department of Medicine, the University of Nebraska Medical Center, Omaha, Neb (SP).
With Commentary from Chaya Venkat, CLLTopics.org
Benjamin Djulbegovic, MD, PhD, Fred J. Hendler, MD, PhD, and Steven Pavletic, MD
Death by Conventional Wisdom
Chaya Venkat, CLL patient caregiver
A 45-year-old man with persistent lymphocytosis that was noted during a routine annual examination was referred for hematologic evaluation. Laboratory studies yielded the following values: white blood cell (WBC) count, 18,200/ mm3 with 81% lymphocytes, 16% neutrophils, 2% monocytes, and 1% basophils; hemoglobin level, 14.5 g/dL; hematocrit, 42.7%; mean corpuscular volume (mm2), 86.8; red cell distribution width, 12.8; and platelet count, 245,000/mm3. Peripheral smear showed normal red blood cell morphology with predominant, small, round lymphocytes. The patient was otherwise in apparent good health. Three years earlier, he had a normal complete blood count. Physical examination and routine laboratory test results were normal.
Consultant: There are many causes of lymphocytosis. From the data that have been provided, this man appears to have chronic lymphocytic leukemia (CLL) that has developed within a period of three years, despite his relatively young age. Presuming that the physical examination is as stated, I would confirm the diagnosis by performing either a bone marrow aspirate/biopsy or flow cytometry on the peripheral blood. For the sake of simplicity, I would choose flow cytometry.
Chaya: Better flow cytometry techniques using a sample of blood are now available. A bone marrow biopsy is increasingly outdated for preliminary diagnosis of CLL. Today a simple blood test can confirm clonal population (kappa or lambda light chain predominance) with the tell-tale CD markers characteristic of CLL. Bone marrow biopsies are not painless, and the sampling error is substantial. In other words, the sample collected at one spot may be different from the sample collected in another spot. I am a strong believer of not doing intrusive or painful testing unless it is going to be worth it. Remember, it hurts you a lot more than the doc that wrote the script.
A bone marrow biopsy showed hypercellular bone marrow with 90% lymphocytes. Immunophenotyping revealed monoclonal B-cell population coexpressing CD5 and CD23 antigens. Chromosome analysis was normal. The diagnosis of stage 0 CLL was made, and the patient returned for a discussion of future management.
Consultant: I agree with that diagnosis, although less than 10% of patients with CLL are under 50 years of age. This immunophenotype is virtually diagnostic of CLL. Further management depends on our estimate of the course of the disease. To this end, identification of favorable or adverse prognostic factors can be helpful. The most important prognostic factors include stage of disease, lymphocyte doubling time, pattern of marrow infiltration by lymphocytes, and chromosomal abnormalities. This patient has only one adverse prognostic factor, a marrow diffusely infiltrated with CLL. The other prognostic factors appear favorable. Since all clinical studies have shown no survival advantage in treating patients with low-stage CLL over observation alone, I recommend that no therapy is warranted and that the patient be followed regularly, every three months.
Chaya: Given this patient’s young age (45 years), I would have asked if there was history of CLL in his family, if this was a case of “familial CLL”. When CLL happens in clusters within families, the second generation to get the disease often get it at a younger age (“anticipation”), and it is sometimes more aggressive than in the prior generation. (Not the Worst Day of Your Life). I wish it was more the norm to treat the whole patient, not just the numbers. Unfortunately, this has not changed in the past 6 years. If anything, doctors are even more pressed for time today. Keeping up with the demands placed on them by HMO’s and the like cannot be an easy task. Rare is the physician who takes the time to ask about familial connections when diagnosing a CLL patient.
The consultant correctly identified the diffusely infiltrated bone marrow as a negative prognostic indicator. Today, he would be remiss if there was no mention of testing for any of the modern prognostic indicators. This consultant may be forgiven for not knowing about these indicators in 1999 but the same mistake is made by a goodly proportion of local oncologists today. How about IgVH gene mutation status, serum beta-2-microglobulin levels, CD38 positivity, or ZAP70? I am not sure about the accuracy of the chromosomal analysis that was done at the time of this case study. If an expert took the same approach today, we would ask why a FISH test was not done to look for the classic abnormalities generally found in CLL? (What Type of CLL Do You Have?; Prognosis at Diagnosis).
The consultant in the case study repeats that old chestnut about “clinical studies have shown no survival advantage in treating low-stage CLL”. The clinical study the consultant is referring to was an old study done at a time when (a) the only drug considered for treating CLL was chlorambucil, and (b) modern prognostic testing was not available to better stratify patients into high risk and low risk groups. Basing therapy decisions on out-dated rules of thumb can be downright dangerous. (Risk-adapted Strategies; Mayo Best Practices). Within the six years from 1999 to 2005, the road map has changed.
The natural history of CLL was discussed extensively with the patient, and he was given estimates of favorable prognosis. The patient agreed to regular follow-up with no planned intervention. He asked about the prospects of bone marrow transplantation (BMT), which was dismissed at the time, given the estimates of good prognosis. Three months later, his WBC count was 25,100/mm3 (66% lymphocytes) with a normal hemoglobin level and platelet count. Physical examination and overall well-being were unchanged. Six months after the diagnosis, the patient started to complain of fatigue and night sweats. Some enlarged lymph nodes had developed in the cervical and inguinal areas without splenomegaly. The WBC count increased to 50,800/mm3 with 86% lymphocytes. His hemoglobin level remained at 13.3 g/dL with a platelet count of 299,000/mm3.
Consultant: When a patient with CLL develops systemic symptoms, the issue is whether the symptoms are due to progression of CLL or to viral or opportunistic infection. To distinguish between these two possibilities, I would obtain a chest radiograph, computed tomography scans of the chest and abdomen, liver function tests, viral titers, and quantitative immunoglobulins.
Chaya: Let’s see, the patient’s WBC increased from the initial 18.2K to 50.8K in six months. That is a rapid doubling time of between 3-4 months. Barring an infection driving this rapid rise in WBC, this should have set off some sort of alarm bell. The consultant correctly identified doubling time of less than a year as a poor prognostic indicator even in the old game book, but somehow seems to have paid less attention to it when it was actually demonstrated. The rapid increase in WBC was also accompanied by enlarged lymph nodes in more than one location, drop in hemoglobin from 14.5 to 13.3, classic b-symptoms of fatigue and night sweats, all of them pointing to a clear case of an aggressive CLL. Even if the prior “chromosomal analysis” showed no abnormalities, I would have considered a repeat FISH analysis at this stage, to see if there has been a clonal evolution, check to see if this guy’s CLL has morphed to a more aggressive variety with 11q (ATM) or 17p tumor suppressor gene deletions.
While a bone marrow transplant was probably not in the cards when the patient previously asked about it, if the modern prognostic testing had been done, and the patient had been found to have unmutated IgVH genes, and /or one of the poor prognosis chromosomal deletions such as 11q or 17p detected by FISH, a bone marrow transplant may well have been identified as the downstream goal, with immediate therapy geared to getting the patient into a deep "complete response" (CR) prior to initiating stem cell transplant therapy. Several experts we spoke with at the ASH2004 conference emphasized this point: get the really poor prognosis - and young - patient into a deep remission, and then do not waste the opportunity presented by this first remission to get him / her into a good transplant program.
The patient returned in a month with progressive fatigue, weakness, and night sweats. Laboratory studies were negative for hepatitis A, B, and C, human immunodeficiency virus, and human T-cell lymphotropic virus-I, as well for active infection of cytomegalovirus and Epstein-Barr virus.
Consultant: Following documentation of no active viral or opportunistic infections complicating CLL, the patient is a candidate for cytoreductive chemotherapy. Observation alone is not adequate management, since survival is clearly compromised without therapy. The choices would be treatment with alkylating agents such as chlorambucil or with a purine analog such as fludarabine. I would choose chlorambucil at this point, since no data show that starting with fludarabine prolongs a patient’s life.
Chaya: OK, now that we have done all the various tests for opportunistic infections and the results came back negative, we are ready to get this show on the road, treat this patient’s CLL as an aggressive variety, not one of the smoldering types. The options considered were the old standards, chlorambucil and fludarabine. Of course, Rituxan or Campath were not routine therapies back then. I wonder what excuse oncologists could possibly have today for not thinking of monoclonal antibody therapy such as Rituxan or Campath, either as single agents or in combination with chemotherapy agents? Even in 1999 the consultant could have checked to see if there were any relevant clinical trials for which he would have been eligible.
Fludarabine has a higher response rate than chlorambucil, but it is probably correct that overall survival advantage has not been proven for either drug. In recent years, there have been several papers describing the risk of secondary cancers (skin cancers and myeloid cancers) as result of fludarabine therapy. Also, tentative but nevertheless sobering information that patients undergoing fludarabine therapy are more likely to fall victim to the dreaded Richter’s syndrome. A recent paper authored by NCI scientists pointed out that fludarabine therapy may select for p53 defective clone, or even create one where none existed before. All in all, I think it is high time to reconsider the slam dunk choice of fludarabine as frontline therapy in CLL. Patients with 17p (p53 gene) defects are not likely to respond to either fludarabine or chlorambucil. Why put them through all that toxicity for nothing? Moral of the story is this: do prognostic testing, before making therapy decisions! (Fludarabine No Longer the Gold Standard).
The patient was told that therapy is indicated at this time and that chemotherapy should be started. Three chemotherapeutic options were presented that included chlorambucil plus prednisone, fludarabine, and cladribine. After consulting two other physicians in the community, he chose cladribine as the treatment option, although he was told that the data about fludarabine efficacy in CLL were more mature. A purine analog was selected due to the lower response rate to chlorambucil. Since patients treated with fludarabine do not respond well to salvage therapy with cladribine, it was explained to the patient that if cladribine failed, fludarabine would remain an option. For this reason, the patient was started on cladribine. During the following two to three months, while the patient considered the therapeutic options, his disease had progressed with generalized adenopathy and splenomegaly. His WBC count increased to 124,000/ mm3 with 89% lymphocytes. His hemoglobin level had dropped to 9.4 g/dL, but the platelet count remained normal at 188,000/mm3.
Consultant: I agree that chemotherapy is indicated. Evidence suggests that chemotherapy can prolong survival in intermediate and advanced stages of CLL. Whether purine analogues are superior to alkylating agents remains unproven, and whether cross resistance occurs when fludarabine follows cladribine failure is controversial. The limited data indicate that cladribine is not beneficial when used as a salvage treatment after failing a trial of fludarabine.
Chaya: I agree the evidence supporting the use of cladrabine before fludarabine is thin at best.
In this patient’s case, in less than 10 months from initial diagnosis, his WBC went from 18K to 124K, his hemoglobin went from a healthy 14.5 to an anemic 9.4, he developed generalized bulky lymph nodes all over, his spleen was swollen. He had all the classic b-symptoms of fatigue, weakness, night sweats. In light of the information we have today, discussing whether cladribine or fludarabine is a better drug to start with in his case is like discussing the exact location of the deck chairs on the Titanic after it has hit the iceberg. Better late than never. Today, If this patient’s prognostic indicators showed an unmutated IgVH gene status with 11q or 17p deletions, as it very well might have given the extreme rapidity with which his disease progressed, the better choice may well be Campath, either as single agent or in combination with other chemotherapy drugs. A recent paper from Dohner, et. al. has shown that even patients with 17p deletions respond to Campath therapy. (Campath: Good News for the Tough Cases; Campath, Looking Better and Better.)
After the first cycle of cladribine, the patient’s hemoglobin level dropped to 7.4 g/dL, and a transfusion with two units of packed red blood cells was administered. Direct and indirect Coombs tests were negative, and there was no evidence of blood loss. After two courses of chemotherapy, lymph nodes had decreased somewhat in size, and the spleen decreased from 6 cm below the left costal margin to 4 cm. His WBC count decreased to 20,000/ mm3, his hemoglobin level was 9.3 g/dL, and his platelet count was 198,000/mm3. Chemotherapy was continued and trimethoprim-sulfametoxazole was administered as prophylaxis against Pneumocystis carinii pneumonia (PCP) infection.
Consultant: The patient seems to be responding to chemotherapy, although the drop in hemoglobin level after one course of chemotherapy is unusual. The drop does not appear to be due to hemolysis of red blood cells or bleeding. Purine analogues can cause profound CD4 lymphocyte depletion. Many physicians use trimethoprim-sulfametoxazole for PCP prophylaxis analogous to prophylaxis in patients with AIDS. However, there are few empiric data to support this practice in cladribine/fludarabine treatment of CLL. I believe that continuing treatment with cladribine is reasonable as long as the patient is responding and there is no significant toxicity.
Chaya: It is all about risks versus rewards. With a hemoglobin level of 7.4, I wonder if the patient was able to drag himself around at all. Cladrabine failed to resolve the lymph nodes, his spleen was still enlarged. There did not seem to be autoimmune disease, or bleeding, no killing of red blood cells in large numbers (“hemolysis”). So one has to wonder what was making the hemoglobin drop so quickly. Given the drug of choice, cladribine, had not succeeded in doing a good job of clearing the lymph nodes or spleen, one would wonder how good a job it was doing on the bone marrow. Perhaps the red blood cells were just not getting made back in the factory in sufficient numbers to make a difference? This is the point where a bone marrow biopsy would have been useful, to get a fix on how badly the bone marrow was infiltrated.
Also, while the patient was given protective antibiotics against pneumonia, today his oncologist should consider prescribing an antiviral such as famcyclovir to protect him against Herpes Simplex as well. The Mayo Best Practices paper suggests pre-emptive protection against painful episodes of shingles should be routinely done prior to purine analog therapy (cladribine and fludarabine are both purine analogs).
Bottom line, the bar has been raised in what we consider “no significant toxicity” today, and in comparison to therapies such as RF, FRC, and FluCAM, this patient’s response would hardly be called acceptable “responding to therapy”.
The patient received another two courses of cladribine. His WBC count further decreased to 3,700/mm3 with 35% lymphocytes, 60% neutrophils, 2% monocytes, and 3% eosinophils. His hemoglobin level remained stable at 9.8 g/dL, and his platelet count was 148,000/mm3. However, he developed bulky cervical, axillary, and inguinal lymphadenopathy. Two weeks after the fourth course of cladribine, he was admitted to the hospital with neutropenic sepsis. His WBC count was 1,000/mm3 with 7% neutrophils, with a hemoglobin level of 10 g/dL and a platelet count of 115,000/mm3. He was treated successfully with broad-spectrum antibiotics and discharged with a WBC count of 3,200/mm3. A bone marrow biopsy revealed almost 100% infiltration with leukemic cells.
Consultant: While the WBC count decreased with cladribine, the marrow remains packed with CLL cells. Furthermore, he has developed bulky disease. His response to cladribine has been poor. Since a complete remission was not attained with cladribine, I would evaluate the patient for the possibility of an allogeneic transplant. Because of the progressive nodal disease, I would switch to fludarabine while awaiting HLA-matching results.
Chaya: There is slim chance that this patient was going to respond sufficiently to fludarabine therapy, given his response to cladribine therapy. Even back in 1999, our consultant had his doubts about it. Going into a bone marrow transplant with a heavy tumor burden is not the best way of doing it. Things work a whole lot better if patients are in a state of “CR”, only minimum residual disease.
The patient was referred to a bone marrow transplant specialist who recommended a transplant if the patient’s tumor burden could be reduced. The patient was started on fludarabine. Since a compatible HLA match was not found among the patient’s siblings, a search for a matched unrelated donor (MUD) began. An unrelated donor match was identified.
Consultant: The patient has been switched to fludarabine and is not a candidate for bone marrow transplant because of persistent bulky disease. He would be considered for transplant only if he showed a response to fludarabine. Evaluating for responding relapse is often used in the setting of lymphoma as a predictor for successful BMT. However, transplantations in refractory relapse have been successful in some CLL patients. I am not aware of data demonstrating the use of BMT with MUDs in CLL.
Chaya: Matched, unrelated donor (“MUD”) transplants for CLL patients were pretty exotic back then. Today they are all the rage. In fact, in the context of non-myeloablative stem cell transplants, the so called “mini-transplants”, MUD transplants seem to get a better graft-versus-leukemia” effect than sibling donor transplants. But at the time of the case study, it sounds like our consultant did not even consider a "new-fangled" non-ablative procedure, instead he went for the full monty of full dose, heavy duty myeloablative transplant which was more the practice at that time. At 45, this patient would be considered young enough to withstand the rigors of a full myeloablative procedure, except that he has been through a lot just before getting into the transplant. Perhaps a mini-transplant was not considered because the patient could not be taken to a full CR prior to transplant. Even today a mini-transplant becomes problematic if the patient cannot be taken to a full CR prior to transplant. Mini-allos work a lot better if there is only minimal residual disease (MRD) left for the graft-versus-leukemia to handle. If only the aggressive nature of his CLL had been identified right at the start, by means of modern prognostic testing, the therapy could have been tailored to suit his situation. A Campath-based therapy would have taken him into a clean CR, just right to get him into a mini-transplant. (The Only Real Cure Out There).
The patient was treated with three courses of fludarabine. The patient had a partial response but experienced severe neutropenia. He underwent a MUD bone marrow transplant after treatment with high-dose cyclophosphamide and total body irradiation. He tolerated the transplant well except for mild graft-vs-host disease (GVHD) involving the skin, which was successfully treated with glucocorticoids. Two months after transplant, a bone marrow biopsy and flow cytometry showed no evidence of CLL. Restriction-fragment polymorphism analysis was consistent with the engraftment. Three months after transplant, he was doing well. His WBC count was 3,700/mm3 with 60% neutrophils and 30% lymphocytes, his hemoglobin level was 8 g/dL, and his platelet count 20,000/mm3. He continued to receive cyclosporine and corticosteroids for GVHD prophylaxis, and penicillin, trimethoprim-sulfametoxazole, fluconazole, acyclovir, and weekly gamma globulins for infection prophylaxis. He still required occasional hemoglobin and platelet transfusions.
Consultant: The patient appears to be doing well. However, he is only several months posttransplant, and the development of chronic GVHD or other BMT complications remains highly likely, particularly following a MUD transplant. Although he seems engrafted, secondary graft failure is still possible. The recurrence of his leukemia is always possible, since we do not know whether CLL can be cured. Much longer follow-up is necessary to establish this.
Eight months after transplant, the patient developed fever associated with shortness of breath and coughing. A chest radiograph showed a cavitary lesion in the right upper lobe consistent with of an aspergillus infection. Despite treatment with amphotericin B, his condition continued to deteriorate, and the patient died 14 days after treatment with amphotericin B.
Chaya: Our consultant was right to be pessimistic of the patient’s chances of surviving the full-bore myeloablative stem cell transplant. This procedure is about as aggressive as it gets. A large percent of patients do not survive it — what I call “death by therapy”. Sure enough, less than 2 years from his initial diagnosis the patient died. Today, except under special circumstances, full bore myeloablative transplants are giving way to mini-allo transplants.
If the events of this case had been dated 2005, we would be correct in thinking that his CLL killed this patient, but an important role would have been played by inappropriate therapy choices based on outdated information and “conventional wisdom”. Oncologists that do not keep up with new developments endanger their patients. This is a scary story, all the more because it is repeated so many times even today. I know this is so because I get many heartbreaking emails from patients or their families attesting to that. The slippery slope of therapy failure and ultimate death of the patient begins right at the start of the whole process, with a one-shoe-fits-all approach. Watch & Wait for all CLL patients irrespective of their prognosis is an outdated paradigm. We are now in the era of risk stratification based on modern prognostic markers and therapy decisions made on the basis of that vital information. (Dawn of a New Era).
Beware of death by conventional wisdom, even when the doctors are sincerely trying to do their best for you. Who is in charge? You are. Don’t you forget that simple fact. It is your life, your body, your decisions. It is a tough road to travel but you are not alone.
Editor’s note: You can read the discussion that follows this case history at the Moffitt Center website: Case Discussion.
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