Relapsed Chronic Lymphocytic Leukemia (CLL)

Ofatumumab

Ofatumumab (HuMax-CD20) inhibits early-stage B lymphocyte activation. It is under development for treatment of B-cell lymphoid malignancies and rheumatoid arthritis. A Phase I-II study was carried out in 33 patients with refractory B-cell CLL. A maximum tolerated dose was not reached in this study. Toxicities were related to early infusions, which diminished with further infusions. More than half the patients developed infections, with one fatal interstitial pneumonia. The response rate was 50%. A second Phase I-II study was carried out in 40 patients with refractory follicular lymphoma treated at four different dose levels. Patients in this study had “profound” B-cell depletion, and 65% reverted to a BCL2 negative status. Response rates ranged from 20% to 63%. The median response duration for responders was 30 months.

At ASH 2008, researchers involved in an International Phase II study reported that ofatumumab was effective for the treatment of patients with CLL who have failed fludarabine and alemtuzumab or who had failed fludarabine and had bulky disease. 

At ASCO 2009, researchers presented an update of the data presented at ASH 2008 with emphasis on the effects of prior exposure to rituximab. This study involved 138 patients who were refractory to fludarabine and alemtuzumab (n=59) or were refractory to fludarabine and had bulky disease (n=79). Table 1 shows the main findings of this study as presented at ASH 2008.

Table 1: Response to Ofatumumab in Double-Refractory and Bulky Fludara-Refractory CLL

The main findings presented at ASCO 2009 were as follows:

• In double refractory patients, the ORR was 54% in patients with any prior exposure to rituximab and 63% in patients who had no prior exposure to rituximab.
• In double refractory patients, median PFS was 5.5 months for patients with any prior exposure to rituximab compared with 7.1 months in patients who had no prior exposure.
• In bulky fludarabine-refractory patients, the ORR was 44% for patients with any prior exposure to rituximab compared with 50% for patients with no prior exposure to rituximab.
• In bulky fludarabine-refractory patients the median PFS was 5.5 months for patients with any prior exposure to rituximab compared with 6.4 months for patients with no prior exposure to rituximab.

These authors concluded that “Single-agent therapy with ofatumumab is effective in patients with doubly-refractory or bulky fludarabine-refractory CLL.”

In a separate analysis, researchers presented data on the clinical improvement observed in the 138 patients treated with single agent ofatumumab described in the previous study. The main findings in this study were:

• In the double-refractory group: 48% had complete resolution of B symptoms, 16% had complete resolution of adenopathy, 62% had a greater than 50% reduction in adenopathy, 47% had complete resolution of splenomegaly, and 50% had complete resolution of hepatomegaly. Five percent of this group had an improvement of neutrophil counts, 30% had resolution of anemia, and 41% had platelet counts that increased by more than 50%.
• In patients with bulky adenopathy refractory to alemtuzumab: 63% had complete resolution of B symptoms, 11% had complete resolution of adenopathy, 49% had a greater than 50% reduction in adenopathy, 35% had complete resolution of splenomegaly, and 52% had complete resolution of hepatomegaly. Twenty-nine percent had an improvement of neutrophil counts, 26% had resolution of anemia, and 39% had platelet counts that increased by more than 50%.

These authors concluded that “Ofatumumab as a single-agent achieves high ORR and improves disease symptoms and hematologic parameters in heavily pretreated pts with DR and BFR disease who lack standard treatment options.”

Oxaliplatin, Fludarabine, Cytarabine and Rituximab

Researchers from the MD Anderson Cancer Center reported that a regimen of oxaliplatin, fludarabine, cytarabine, and rituximab was effective in patients with relapsed or refractory CLL or Richter’s syndrome. In 30 patients with CLL the CR rate was 6% and the PR rate was 73%. The one-year EFS was 67% and the one-year OS was 75%. There were eight patients with Richter’s syndrome; one had a CR, two had a PR, and one-year overall survival was 53%.

New Agents for the Treatment of CLL

Valproic Acid

Valproic acid is primarily used as an anticonvulsant to control seizures and has also been used to treat bipolar disorder. Valproic acid is an inhibitor of the enzyme histone deacetylase (HDAC) which mediates apoptosis in CLL cells ex vivo. A recent study has shown that this effect is mediated “through caspase activation via both the extrinsic and the intrinsic apoptosis pathways, as indicated by the activation of the caspase proteins 8 and 9, and cleavage of the proapoptotic protein BID.” These results “identified the HDAC inhibitor valproic acid as restoring the apoptotic pathways in CLL cells and thus their ability to undergo apoptosis.”

At ASCO 2009, researchers from India presented data suggesting that valproic acid produced “impressive palliation in advanced/refractory CLL”. They treated five previously treated patients with CLL. Three of the five patients were evaluable for response. One had a partial response and one had stable disease. The third patient had shrinkage of lymph nodes but no effect on the peripheral blood count. Two of the three patients requiring blood transfusions stabilized their hemoglobin levels and no longer required blood transfusions. The main side effect of valproic acid was drowsiness. These are very early data but there appears to be significant activity for this well-tolerated drug in CLL patients.

GCS-100, A Galectin-3 Antagonist

GCS-100, is a carbohydrate molecule designed to inhibit the activity of Galectin-3, a protein found in high concentration in a broad range of human cancers and whose over-expression is associated with poor prognosis in cancer patients. GCS has been shown to inhibit apoptosis. At ASCO 2009, researchers involved in a multicenter international study reported that GCS-100 has significant activity in elderly patients with relapsed CLL. This study included 24 patients with previously treated CLL with an average age of 67 years (40-84). There were no grade 3-4 toxicities. The PR rate was 25% and six patients remain on treatment with a median duration of five months. In vitro studies confirmed apoptosis. This well-tolerated agent will undoubtedly be added to other drugs in future studies in patients with CLL.

Immunotherapy With Recombinant CD40-Lignand (AD-ISF35)

Researchers from the University of San Diego and Memgen LLC reported that “Single intranodal direct injection (IDI) of Ad-ISF35 was safe and effective in inducing systemic biologic and clinical responses in patients with CLL. IDI of Ad-ISF35 might be effective in the treatment of CLL and related lymphomas.” The following is a quote from the Memgen web site on how this therapy works:

“To deliver the ISF35 molecule to target malignant B lymphocytes, Memgen uses a replication defective type 5 adenovirus. The adenovirus infects the leukemic cells, resulting in the stable expression of the ISF35 molecule on the cell surface. The adenoviral proteins trigger the immune system to attack infected malignant cells, and ISF35 augments this response, resulting in a localized full-force reaction against the treated cells. When the triggering antigen (adenoviral protein) disappears because the carrier adenovirus does not replicate, the treated cells undergo spontaneous apoptosis. In this manner, ISF35 results in the rapid reduction of circulating and lymph node-bound leukemic cells, the up-regulation of pro-apoptotic proteins sensitizing these cells to standard treatments, and the generation of anti-leukemic immune responses that may have long term impact on disease progression. The adenovirus, containing the ISF35 molecule, can be used to infect leukemic cells ex vivo or by direct injection into tumor beds.”

The Phase I study presented at ASCO 2009 involved 15 patients with refractory CLL who received a single IDI of Ad-ISF35. The IDI was well tolerated. “IDI of Ad-ISF35 induced blood CLL cells to express death receptors, pro-apoptotic proteins and immune co-stimulatory molecules similar to those induced on “bystander” CLL cells co-cultured with Ad-ISF35 transduced cells in vitro.” IDA also resulted in a median reduction of peripheral blood CLL cells by more than half. There was also a reduction in lymph node and spleen size which lasted four months or longer in nine patients. Treatment-free survival was 5.3 months and three patients remain stable without additional therapy.

These same authors also had an abstract published but not presented at ASCO 2009 showing that autologous AdISF-transduced CLL cells can induce de novo, systemic expression of death receptors and can enhance the cytotoxic effects of standard chemotherapy in P53-defective CLL. 

TRU-016, An Anti-CD37 Directed SMIP

SMIP (small modular immuopharmaceutical) are single chain polypeptides comprising one binding domain, one hinge domain and one effector domain designed in an effort to meet predetermined therapeutic specifications for specific diseases. SMIP therapeutics are mono-specific (they recognize and attach to single antigen targets and initiate biological activity). TRU-016 is described as “a single chain anti-CD37 Fc fusion molecule that displays pro-apoptotic and Fc-dependent cellular cytotoxicity activities against CLL cells and NHL lines.”

At ASCO 2009, data on 26 patients with relapsed or refractory CLL treated on a Phase I study of TRU-016 were presented. The median reduction of lymphocyte counts was 67% with a maximum reduction of 98%. Two patients with skin involvement had complete resolution of skin lesions. Reductions in lymph node and spleen size were also observed.

Summary

The above abstracts suggest that more treatment options are now available for patients with CLL.

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