Not all monoclonals are the same!

Campath was the very first monoclonal antibody that was approved for use in CLL, across the board.  Heck, they even got the FDA to approve frontline use of this drug!  (I think they did it the sneaky way, in my humble opinion, by comparing Campath against lower than normal dose of chlorambucil - an unfair strawman comparison.  But that is another story).

Campath has one huge thing going for it that Rituxan does not.  Campath is thought to work even in high risk cases with poor cytogenetics, those with the dreaded 17p deletion.  As we have seen in a prior article “Crystal clear results on FCR“, patients with 17p deletion get little joy from FCR.  Since Campath can do what Rituxan cannot in this group of high risk patients, I suppose it is a reasonable question to ask if replacing Rituxan with Campath is a good ides.  Hence this clinical trial of FC+Campath in high risk and previously treated patients.

FC + Campath

The results of this clinical trial were presented at the latest ASH2010 conference.  43 patients were planned for this study, and they managed to get all 43 patients to enroll.  There is no question this was a high risk group.  More than half of the group had either 11q or 17p deletion, indications of high risk.  All had been previously treated, this combinations of FC+Campath was being considered as salvage therapy.

Fludarabine, Cyclophosphamide, and Alemtuzumab (FCC) In Relapsed/Refractory Patients with B-Cell Chronic Lymphocytic Leukemia (CLL): Final Report of the Italian Study

Marco Montillo, MD1, Alessandra Tedeschi*,1, Francesca Ricci*,1, Alfonso Zaccaria*,2, Monica Crugnola*,3, Mauro Spriano*,4, PierAngelo Spedini*,5, Fiorella Ilariucci*,6, Lilj Uziel*,7, Immacolata Attolico*,8, Angelo De Blasio*,9, Eleonora Vismara*,1, Enrica Morra1 and Valeria Belsito Petrizzi*,10

Abstract 1384

Introduction: Purine Analogues in combination with cyclophosphamide (C) have a relevant advantage over monotherapy approach in patients(pts) with CLL. However, pts in complete remission (CR) eventually relapse and require treatment, demonstrating the need for improved treatments able to induce “better quality” and thus more durable responses. Monoclonal antibody alemtuzumab (CAM), directed towards CD52 antigen expressed on the surface of CLL cells has been proven to be the most effective antibody in CLL treatment. As previously reported by Elter et al. (JCO 23:7024-7031.2005) CAM appears to have synergistic activity with fludarabine (F) in vivo in relapsed and refractory CLL. Therefore, we designed a phase II study to determine the efficacy and safety of a 4-weekly combination regimen consisting of F, C, and CAM in CLL with relapsed or refractory disease after at least 1 line of treatment.

Methods: The FCC regimen consisted of oral F 40 mg/m2/day and oral C 250 mg/m2/day immediately followed by sc CAM 10 mg/day (Days 1–3). A-2 day escalation of CAM was administered prior to the first cycle. This combination was repeated on Day 29 for up to 6 cycles. According to the safety profile of the schedule described above the dose of CAM was increased after the first cohort of 10 treated patients from 10 mg to 20 mg. Minimal residual disease (MRD) was measured by 4-color flow cytometry.

Anti-infective prophylaxis included acyclovir 400 mg twice daily and trimethoprim sulfamethoxazole (TMP + SMX) 1000 mg given every other day from treatment initiation until 6 months after treatment end. CMV antigen in blood was tested in 7–days interval.

Results: Recruitment was stopped when the planned number of 43 patients have been enrolled in the trial. The median age of the patients was 60 years (range, 39–77), 26/43 (60%) were male, 42/43 (98%) had Binet stage B and C disease, and the median number of prior treatment regimens was 2 (range, 1–4); 32/43 (74%) of patients were relapsed while 11/43(26%) were refractory to prior therapy.

Pretreatment included F in 93% of patients (F+C 35%) and monoclonal antibodies (MoAb) in 39.5% of patients (Rituximab 28%, CAM 19%; both MoAb 7%). More than a half of pts presented with deleted 11q or 17p with 28% of pts showing 17p as the sole aberration. Unmutated IgVH was detected in 23/34 (68%) pts while 17/43 (52%) were tested positive for ZAP70. Median number of given cycles was 4. Myelosuppression of all grades was the most commonly occurring adverse events. Grade III-IV neutropenia episodes were observed in 66% of the administered courses while grade III-IV thrombocytopenia episodes were detected only in 8.0 % of cycles. Symptomatic CMV reactivation occurred in 8 cases, no CMV disease was recorded. Twelve major infections occurred, including hepatitis B virus (HBV) reactivation (1 patient), pneumonia (8 episodes), and sepsis (3 episodes). Two major late infections were also observed: 1 tuberculosis and 1 aspergillosis. There were 8 deaths among 29 responding patients due to disease progression (5 patients), Richter’s syndrome (2 patients), and one major late infection (tuberculosis). Progressive disease was the cause of death in 11 cases among 14 non-responding patients. An overall response rate (ORR) of 67% (29/43) was recorded with 13 pts (30%) achieving CR (MRD- in 6 pts) and 16 PR (37%). Higher ORR (p=0.003) was observed in pts not previously treated with MoAb. After a median follow up of 16.7 months (range, 1–49.5 mo) patients receiving FCC had a median PFS of 24.4 months. Finalized data of all patients will be presented.

Conclusion: Results from the final analysis of this new, 4-weekly dosing FCC regimen suggest that combination therapy with F, C and CAM is effective. Poor prognostic factors were strongly represented in these patients, including 68% unmutated IgVH and 54% deleted 17p or 11q. Although there were a number of major infections, most were manageable.

Disclosures: Montillo: Bayer: Research Funding, Speakers Bureau; Genzyme: Research Funding, Speakers Bureau.


I suppose substituting Campath for Rituxan in FCR is a reasonable research concept.  Reasonable, but not really out-of-the-box creative, and certainly not prudent - in my opinion.  Sometimes I get the feeling that researchers are ticking off drug combinations in a grid of all possible combinations and permutations, not really putting brain in gear - or for that matter, putting patients’ safety front and center.

The last couple of sentences in the abstract “combination therapy with F, C and CAM is effective” and “Although there were a number of major infections, most were manageable” had me hitting the roof.  “Manageable” did you say?  “Effective combination”?

I beg to differ.  Please let me to count the ways.

  • There were 8 cases of CMV reactivation.
  • 12 major infections occurred (that is a whopping 28%) including hepatitis B, pneumonia, sepsis, tuberculosis, aspergillosis.
  • 2 patients had Richter’s transformation.
  • All in, 19 patients out of 43 died!!! How is that for “manageable“? And “effective“?
  • In spite of this very high intensity combination, 16 patients had progressive disease while on therapy.

I don’t know about you, but with this kind of track record, I would not want to be on this combination.

Mind you, I am very aware this is a high risk group of patients.  In the last two years, it has become increasingly clear that for patients with 17p deletion there are only a limited number of choices.  Campath is one of them. But this combination of Campath with F+C has got to be one of more over-the-top high toxicity combinations.  And the very high percentage of patient deaths in this study proves it.  I wonder if the patients would have done better if they just went home to hospice, rather than follow this therapy protocol.  At the very least, they would have had more peace and quiet.

These clinical trial results are one more reason why I am so interested in all the work being done with lenalidomide (Revlimid) - another drug that works in 17p deleted cases - but with low toxicity with respect to T and NK cells.   Unlike this combination of FCC, where both fludarabine and Campath are justly infamous for destroying T-cell and NK cell populations, Revlimid actually increases T-cell and NK-cell counts and their efficacy.  That in turn means we may hope for fewer life threatening infections with Revlimid based therapy.  Other drugs are in the pipeline as well, though in early stages.  CAL-101 is another drug that may work with high risk patients. Other kinase inhibitors may do so as well.  We can only hope and keep our fingers, toes and eyes crossed.

There is only one scenario where we can consider total destruction of T-cell and NK-cell populations with a certain amount of equanimity:  just ahead of a mini-allo stem cell transplant, when new T-cells and NK-cells from the graft are going to take the place of your own home grown variety.  These cell lines are so very important in protecting us against infections of all sorts, as well as secondary cancers (skin cancer) and transformation to more dangerous and aggressive lymphoma (Richter’s transformation).

Adding to the toxicity bill by piling on more and more T-cell destroying drugs is not the answer.  Even if patients get remissions from such combinations, it is a case of winning the battle but losing the war.

You notice I did not even bother to parse the response statistics.  Do you particularly care whether or not you got a CR response, if you are also at much higher risk of kicking the bucket due to uncontrolled infection a short while later?  Both Campath and fludarabine kill T-cells.  And it takes a long time for these cell lines to come back, especially following Campath therapy.  Combining these two drugs (Campath + fludarabine) should have a huge red danger mark associated with it.

More is not necessarily better.  I am coming to the conclusion that piling on the toxicity is not the answer.  I keep telling patients to weigh the risks and rewards of any therapy choice.  I wonder if I should be preaching that sermon to researchers as well - if they would bother to listen.  We know enough by now to have been able to predict the deadly toxicity of this combination, even without having done this trial.  Were these patients counselled that they may have a better chance if they chose to go for a mini-allo transplant?  I do realize not everyone can have a transplant, there are lots of barriers including lack of a well matched donor. But surely we can do better than FC+C for our relapsed and high risk patients?