Saturday, April 05, 2008

CLL: Immunochemotherapy

Rituximab—the chimeric monoclonal anti-CD20—is only moderately active as a first-line agent in chronic lymphocytic leukaemia,[131] with an overall response rate of 51% and a complete remission rate of only 4%. However, when it is added to fludarabine or fludarabine plus cyclophosphamide, impressive responses have been reported. In a randomised phase II study,[132] rituximab added to fludarabine produced higher responses when given concurrently than when given sequentially. When compared with historical selected controls in a multivariate analysis controlling for pretreatment characteristics (but not for modern prognostic markers), addition of rituximab seemed to enhance significantly progression-free and overall survival.[133]

The combination of fludarabine, cyclophosphamide, and rituximab has been tested in first-line and relapsed and refractory settings (see also section on Drug-resistant chronic lymphocytic leukaemia). As first-line therapy,[134] overall response rates of 95% and complete remission rates of 70% were reported. In historical controls treated with fludarabine plus cyclophosphamide, the same research group recorded overall response rates of 88%, with 35% complete remission. However, only 33% of patients treated with fludarabine, cyclophosphamide, and rituximab were Rai stage III and IV, compared with 50% of those given fludarabine plus cyclophosphamide, and no modern prognostic markers have been reported for either patients or historical controls. In another phase II study, addition of mitoxantrone to fludarabine, cyclophosphamide, and rituximab seemed to add only toxic effects rather than increased efficacy.[135] Phase III comparisons of fludarabine, cyclophosphamide, and rituximab and fludarabine plus cyclophosphamide are currently underway, and these findings should be reported in 2008 or 2009.

Another purine analogue, pentostatin, has been assessed in combination with cyclophosphamide and rituximab in a phase II trial of previously untreated patients with chronic lymphocytic leukaemia.[136] This trial is valuable in that the prognostic markers IGHV gene mutations, CD38 expression, ZAP70 expression, and interphase cytogenetics were reported. The overall response rate was 91%, with 41% complete remission. Patients with TP53 anomalies had poor responses. The researchers claim that this regimen is less toxic than fludarabine, cyclophosphamide, and rituximab.

Although not yet published, even in abstract form, the Roche website has this statement concerning the German/French CLL8 trial: The pivotal CLL8 trial, initiated by the German CLL study group, successfully met its primary endpoint, by showing that patients treated with MabThera in combination with the current standard chemotherapy achieved a significant improvement in progression free survival, compared to patients treated with chemotherapy alone.

This result became apparent following the first interim analysis in January 2008. An abstract is being prepared for ASH 2008.

Alemtuzumab seems to be one of the few agents capable of killing chronic lymphocytic leukaemia cells with mutated or deleted TP53 genes. The drug has been used as first-line therapy in a phase III trial, in which it was compared with chlorambucil at a dose of 40 mg/m2 per month. Overall response rates and progression-free survival were significantly better for alemtuzumab than for chlorambucil.[137]

Unfortunately, Alemtuzumab seems to be incapable of penatrating large tumor masses and is regarded as contraindicated if lymph nodes have a diameter of greater than 5 cm. However, when used in combination with high dose methylprednisolone (another drug that is effective in CLL lacking p53 function) in a small phase II study, teh overall response rate was 100% with a 60% CR rate. [161]


131 JD Hainsworth, S Litchy and JH Barton et al., Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network, J Clin Oncol 21 (2003), pp. 1746–1751.

132 JC Byrd, BL Peterson and VA Morrison et al., Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712), Blood 101 (2003), pp. 6–14.

133 JC Byrd, K Rai and BL Peterson et al., Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011, Blood 105 (2005), pp. 49–53.

134 MJ Keating, S O'Brien and M Albitar et al., Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia, J Clin Oncol 23 (2005), pp. 4079–4088.

135 S Faderl, WG Wierda and S O'Brien et al., Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) as frontline therapy for CLL: results of a phase 2 study, Blood 108 (2006), p. 2836.

136 NE Kay, SM Geyer and TG Call et al., Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia, Blood 109 (2007), pp. 405–411.

137 P Hillmen, AB Skotnicki and T Robak et al., Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia, J Clin Oncol 25 (2007), pp. 5616–5623.

161 AR Pettitt, E Matutes and D Oscier, Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects, Leukemia 20 (2006), pp. 1441–1445.


Anonymous said...

Two comments: First of all, the usability of Campath is limited to patients lacking bulky lymph nodes (5 cm or less in any axis, either as a single node or collection of nodes). Unfortunately, significant adenopathy is not uncommon in end-stage CLL patients, obviating the use of Campath in these patients.

Secondly, pentostatin has the reputation of being less myelotoxic, but that is still an area of controversy, with some clinicians holding that the reduced toxicity is effectively due to lower doses of the purine analog in question, i.e. pentostatin; the drug itself may be just as myelosuppressive.

One must balance the impressive complete remission rates found combination chemotherapies with the greater instances of T-cell suppression and the probably increase in secondary malignacies evident in patients subsequent to the administration of purine analogs. Additionally, the risk of autoimmune disorders such as AIHA and ITP are elevated after immunosuppressive regimes.

As yet, researchers who are 'fans' of FCR cannot point to a plateau in the survival charts, leading to the speculation that enhanced survival may be a temporary phenomenon.

Terry Hamblin said...

Yes it is certainly true that Alemtuzamab does not penetrate bulky nodes, but when used in combination with high dose steroids, it is effective even in patients with large nodes.

I agree with you about pentostatin, but there are no data to support this contention.

I have been to the forefront in warning about T cell suppression. It is a major problem with fludarabine, and with Campath, though it is not so long lasting. However, FC is less likely to produce severe hemolytic anemia than is fludarabine alone. Even chlorambucil can trigger AIHA though in this case it is more easily controlled.