Paul Barr, MD: Relapse Following Purine Analog Therapy

Is the fact that the patient relapsed after purine analog therapy important to consider?

We have to keep in mind and make note of when patients demonstrate inferior responses to conventional chemotherapy, most notably the purine analogs. In the previous era when we relied heavily on chemoimmunotherapy, we found that patients who had a short duration of remission or did not respond to purine analogs had a very poor OS, a median of 1 to 2 years in most series. With some of the newer agents, we are making significant improvements in the outcomes for these patients. I think it relates to the fact that these agents have a different mechanism of action. I’ve already mentioned ibrutinib and idelalisib. In clinical trials, we have seen improved outcomes for patients with specifically fludarabine- or bendamustine-refractory disease. There are several other important options to consider.

[One] of the nonapproved agents, lenalidomide, has demonstrated responses in these patients. While it’s not approved and hasn’t been as heavily studied, it can be an important option for refractory CLL patients. Alemtuzumab with high-dose steroids has demonstrated somewhat promising outcomes in these difficult-to-treat patients. When using such a regimen you have to be attentive to side effects. One of the other important considerations is patients with high-risk markers, especially having poor responses to standard therapy, [for whom] we have to consider clinical trials.

It wasn’t that long ago that ibrutinib and idelalisib were only available in clinical trials, and we saw dramatic responses in patients that previously had no other treatment options available. So to see patients get good benefit while taking pills and return to their previous quality of life really solidified in my mind the importance of clinical trials. In moving forward to see similar dramatic results from the Bcl-2 inhibitor venetoclax, as well as [from] newer agents in the BCR inhibitor class, [and from] completely novel strategies giving patients benefit, we have to weigh those risk factors, including when patients are refractory to chemotherapy.

Case 2: Relapsed and Refractory CLL

James S. is a 67-year-old college professor from Ithaca, New York; he is a Vietnam veteran with a history of treatment for Agent Orange exposure; his history is also notable for prior smoking (15-pack year) and mild COPD.

In November 2013, he presented to his PCP for a routine physical; his examination showed mild lymphadenopathy and his CBC showed evidence of lymphocytosis (lymphocytes 6 x 109/L); he was referred to an oncologist for further diagnostic evaluation.

Differential diagnosis showed B-cell CLL, with absolute lymphocytosis (19,000/mm3) and flow cytometry positive for CD5 and CD23.

Interphase cytogenetic analysis showed no deletion of 17p.

The oncologist initiates treatment with bendamustine/rituximab (BR) and James shows improvement in hematologic parameters after 6 cycles.

James was out of the country at a meeting, and he failed to return for a scheduled follow-up appointment in January 2015.

In March 2015, he presented to his oncologist with symptoms of unintentional weight loss over the past 2 months (>10%), severe fatigue (interfering with work), and dyspnea; his CBC is consistent with worsening anemia and thrombocytopenia.

CT scan shows evidence of extensive abdominal lymph node recurrence.

At the time of his recurrence, James’s ECOG performance status was 2, and liver and kidney functioning were within normal limits.