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Alert Number 255

Dithering Is Human

Date: October 8, 2007

Battle plans are difficult to draw up – and it is even more difficult not to second-guess ourselves. Harvey and Serena are no exceptions (especially Serena). Decisions that look solidly reasonable begin to take on a more sinister appearance, especially late at night when one is struggling with insomnia.

Our hypothetical hero “Harvey” is going through 6 monthly cycles of HuMax-CD20 + fludarabine – in other words, the HuMax version of the more familiar RF combo pioneered at Ohio State and reviewed extensively on our website. So far he has completed three cycles with few adverse effects. He is still active, still able to carry out his regular and vigorous exercise regimen. The only clinical item of note is neutropenia, controlled with 3 or 4 Neupogen shots during the course of each cycle.

Harvey’s absolute lymphocyte count (ALC) is at rock bottom as one would expect from the HF therapy. But blood counts were never Harvey’s problem. As one would expect with his 11q deletion, bulky lymph nodes are the issue here. Sure, the nodes have shrunk quite a bit since the start of therapy. Bulky nodes that used to be 4 cm across are now about 1.5 cm across, a reduction of more than 90% tumor volume (you can do the math yourself, or take my word for it!). But the pesky things have not gone away completely. After the initial big reduction, the effect of each successive cycle seems to be far less dramatic. The nodes shrink some in the first week after therapy, than bounce back almost to their former glory in the next couple of weeks. What I would call 2 steps forward and 1 ½ steps back. Scary.

It is looking more and more like Harvey will not be getting one of those squeaky-clean MRD negative responses. He will be lucky to get a garden variety CR at best. In any case, judging from the speed with which the nodes bounce back in size, the remission at the end of the 6 cycles of HF does not promise to be a long-lived one. Folks who relapse quickly after fludarabine containing therapy are classified as “fludarabine refractory” – a scary place to be. It is also most likely that large lymph nodes at the time of relapse will rule out Campath as a good choice.

In this context, the very recent article from M. D. Anderson (abstract below) is very relevant. Patients who are fludarabine refractory (Harvey seems to fit that bill, since his disease seems to spring back so fast) and for whom Campath is not indicated (because of large lymph nodes, as in Harvey’s case, since Campath does a poor job of dealing with bulky disease) have few choices. The difference between more chemo as salvage therapy on the one hand and a stem cell transplant on the other hand is pretty dramatic. I highlighted the sentences that caught my attention. The only people who got a complete remission were those patients who opted for a stem cell transplant. None of the folks who had more chemotherapy as salvage did so well.

It now looks like Harvey’s battle plans were on target after all. Below are the links to Harvey’s battle plans, the Catch-22 scenarios patients face as they try to make these very tough decisions and what our expert panel had to say about the whole ball of wax. The moral of the story: dithering over scary decisions is human and the best of us indulge in it. But when the rubber meets the road, all of us have to learn to suck it in and make the tough calls. Otherwise, dithering may prove to be downright dangerous to your health.

Battle Plans
Catch 22 - Transplant decisions
What say you, Dr. Expert?
The "Forest Bump" story

Be well,

Chaya
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Editor's Note: You can read a more detailed analysis of these results in our article Refractory CLL.
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Abstract:

Leuk Lymphoma, October 1, 2007; 48(10): 1931-9.

The natural history of fludarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy.

CS Tam, S O'Brien, S Lerner, I Khouri, A Ferrajoli, S Faderl, M Browning, AM Tsimberidou, H Kantarjian, and WG Wierda

Department of Leukemia and Stem Cell Transplantation, M. D. Anderson Cancer Center, Houston, TX

The natural history and outcome of salvage treatment for patients with fludarabine-refractory chronic lymphocytic leukemia who are either refractory to alemtuzumab ("double-refractory") or ineligible for alemtuzumab due to bulky lymphadenopathy ("bulky fludarabine-refractory") have not been described. We present the outcomes of 99 such patients (double-refractory n = 58, bulky fludarabine-refractory n = 41) undergoing their first salvage treatment at our center. Patients received a variety of salvage regimens including monoclonal antibodies (n = 15), single-agent cytotoxic drugs (n = 14), purine analogue combination regimens (n = 21), intensive combination chemotherapy (n = 36), allogeneic stem cell transplantation (SCT; n = 4), or other therapies (n = 9). Overall response to first salvage therapy other than SCT was 23%, with no complete responses. All four patients who underwent SCT as first salvage achieved complete remission. Early death (within 8 weeks of commencing first salvage) occurred in 13% of patients, and 54% of patients experienced a major infection during therapy. Overall survival was 9 months, with hemoglobin < 11g/dL (hazard ratio 2.3), hepatomegaly (hazard ratio 2.4), and performance status>/= 2 (hazard ratio 1.9) being significant independent predictors of inferior survival.

PMID: 17917961
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