Posted on March 8th, 2009 by
New and Novel Agents for the Treatment of Non-Hodgkin’s Lymphoma: A Report from the 2008 Meeting of the American Society of Hematology
The 2008 ASH meeting featured several reports of new agents that are showing promise in the treatment of Non-Hodgkin’s Lymphoma (NHL).
Revlimid for Mantle Cell Lymphoma and Diffuse Large B-cell Lymphoma
Revlimid® (lenalidomide) is an orally administered derivative of thalidomide, a very active agent for the treatment of multiple myeloma. Revlimid also has anti-angiogeneic properties as well as numerous possible immune and biologic properties. Clinical trials have also documented activity for Revlimid in renal cell carcinoma, myelodysplastic syndromes, and CLL. Revlimid also has significant activity in patients with relapsed or refractory aggressive NHL, including mantle cell lymphoma.1
At ASH 2008 researchers involved in the international Phase II trial, NHL-003, reported that Revlimid is an effective treatment for patients with relapsed or refractory mantle-cell lymphoma or diffuse large B-cell lymphoma (DLBCL).2,3 This trial involved 39 patients with mantle cell lymphoma who had received a median of three prior therapies. The median time from diagnosis to treatment was 3.4 years. Twenty-three percent of patients had received prior treatment with Velcade® (bortezomib). The complete response rate was 13%, the partial response rate was 28%, and 26% had stable disease. Myelosuppression was the main side effect. Among the 73 patients with diffuse large B-cell lymphoma who had also received a median of three prior therapies, the complete response rate was 4% and the partial response rate was 25% while 15% had stable disease.
Thus, Revlimid appears to have significant activity with manageable side effects in patients with refractory mantle cell lymphoma or DLBCL. Studies of the effects of Revlimid earlier in the disease course appear to be indicated.
Researchers from France have reported that RO5072759 was effective in patients with relapsed and refractory NHL.4 RO5072759 is a humanized and glycoengineered monoclonal anti-CD20 antibody. The authors of this abstract state that “glycoengineering results in a significantly increased antibody-dependent cytotoxicity.” They treated 24 patients with relapsed or refractory NHL, with the majority having follicular lymphoma. All had previously received Rituxan. In the Phase II portion of the trial, seven of 12 patients responded to treatment, with three complete responses, four partial responses, and an additional patient with stable disease. This is another promising antibody for the treatment of B-cell malignancies.
At ASH 2008 researchers involved in a U.S. multicenter trial reported that the oral inhibitor of spleen tyrosine kinase (SYK), fostamatinib disodium (FosD) (R788), has significant activity and is well tolerated in patients with diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL).5 FosD works by disrupting B-cell receptor mediated signaling by inhibiting SYK. This represents a novel approach to the treatment of B-cell malignancies. FosD blocks IgG receptor (Fc receptor) signaling in macrophages and B-cells and addresses multiple inflammatory mechanisms including TNF-α, IL-1, and -6. FosD has shown clinically significant results in treating patients with rheumatoid arthritis.6 At ASH 2008 researchers from Europe also presented data showing that SYK is over-expressed in CLL and represents a potential therapeutic target.7
This study included 68 patients with relapsed or refractory NHL. Patients in this study had DLBCL, follicular lymphoma, SLL/CLL, mantle cell lymphoma, marginal zone lymphoma, and MALT. The response rate was 21% for patients with DLBCL, including one complete response, 54% for patients with SLL/CLL, 10% for follicular lymphoma, and 11% for patients with mantle cell lymphoma. Stable disease was observed in 23 patients. FosD was described as well tolerated. These authors stated that “FosD should be developed further, as a single agent and in rational combinations, for BCR-dependent B-cell NHLs.” FosD appears to be a very novel agent with significant potential for the treatment of B-cell NHL.
Blinatumomab is a fusion protein that belongs to a new class of constructed antibodies called BiTE. Blinatumomab specifically targets CD19 on B-cells. This antibody is described as acting by engaging T-cells to lyse cancer cells. A study in the August issue of Science has shown that low doses of blinatumomab had marked anti-lymphoma effects.8 An in vitro study has suggested that the addition of blinatumomab augments the activity of Rituxan® (rituximab).9 At ASH 2008 researchers from Germany treated 39 relapsed patients with NHL.10 Dose-dependent responses were observed in mantle cell lymphoma, follicular lymphoma, and CLL. At a higher dose level, seven of seven patients responded and only one of these relapsed after 14 months. This is a very interesting agent that apparently has remarkable activity in NHL.
Inotuzumab ozogamicin (IO) is an anti-CD22 antibody linked to the toxin calicheamicin. Thus it is similar in construction to gemtuzumab ozogamicin, which is an anti-CD33 antibody linked to calicheamicin used for over a decade to treat acute myeloid leukemia. Studies in an animal model have shown that the combination of IO is active against NHL.11 At ASH 2008 researchers involved in an international study reported that IO in combination with Rituxan has significant activity in patients with relapsed follicular lymphoma and DLBCL.12 This was a Phase I-II study in 30 patients. Anti-tumor responses were seen at all dose levels. At the MTD the overall response rate was 71% with a 43% complete response rate. Progression-free survival was 100% for patients with follicular lymphoma and 66% for patients with DLBCL. The main toxicity was thrombocytopenia.
At ASH 2008 researchers involved in the PROPEL (Pralatrexate in patients with Relapsed OR refractory Peripheral T-cell Lymphoma) trial reported that 27% of patients with relapsed or refractory PTCL experienced a complete or partial remission following treatment with the drug pralatrexate.13 Pralatrexate inhibits dihydrofolate reductase (DHFR), a folic acid-dependent enzyme involved in the building of nucleic acids and other cellular processes. Pralatrexate is a small-molecular chemotherapy agent that is transported into tumor cells via the reduced folate carrier (RFC-1) and was designed for effective retention once inside tumor cells.
Researchers conducted a Phase II clinical trial in 115 patients with relapsed or refractory PTCL. Study participants received intravenous pralatrexate in addition to vitamin B12 and folic acid supplementation. Data on 109 patients were available for analysis. Ten percent of patients had a complete response, and 17% had a partial response. These results suggest that pralatrexate is active against relapsed or refractory PTCL.
Data on a number of new antibodies and novel agents were presented that appear to have remarkable activity in patients with B-cell malignancies.
1 Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Journal of Clinical Oncology. 2008;26:4952-4957.
2 Witzig TE, Vose JM, Reeder CB, et al. Confirmation of the efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: Results of an international study (NHL-003). Blood. 2008;112:103, abstract 262.
3 Vose JM, Zinzini PL, Reeder CB, et al. Confirmation of the efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory diffuse large-B-cell lymphoma: Results of an international study *NHL-003). Blood. 2008;112:103, abstract 268.
4 Salles GA, Morschhauser F, Cartron G, et al. A phase I/II study of RO5072759 (GA101) in patients with relapsed/refractory CD20+ malignant disease. Blood. 2008;112:93, abstract 234.
5 Friedberg JW, Sharman J, Schaefer-Cutillo J, et al. Fostamatinib disodium (FosD), an oral inhibitor of Syk, is well-tolerated and has significant activity in diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia. Blood. 2008;112:3, abstract 3.
6 Weinblatt ME, Kavanaugh A, Bargos-Vargos R, et al. Treatment of rheumatoid arthritis with syk kinase inhibitor: A twelve-week randomized, placebo-controlled trial. Arthritis Rheumatism. 2008;58:3309-3318.
7 Buchner M, Fuchs S, Prinz G, et al. Spleen tyrosine kinase (SYK) is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Blood. 2008;112:203, abstract 543.
8 Barquo R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974-977.
9 dArgouges S, Wissing S, Brandl C, et al. Combination of rituximab with blinatumomab (MT103/MEDI-538), a Tcell-engaging CD1-/19/CD3-bispecific antibody, for highly efficient lysis of human B lymphoma cells. Leukemia Research. 2008; Epub ahead of print on October 1.
10 Bargou R, Topp M, Kufer P, et al. Sustained response duration seen after treatment with single agent blinatumomab (MT103/MEDI-538) in the ongoing phase I study of MT103-104 in patients with relapsed NHL. Blood. 2008;112:105, abstract 267.
11 DiJoseph JF, Cougher MM, Kalyandrug LB, et al. Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of alicheamicin, and rituximab against non0Hodgkin’s B-cell lymphoma. Clinical Cancer Research. 2008;12:242-249.
12 Fayad L, Patel H, Verhoef F, et al. Safety and clinical activity of the anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) in combination with rituximab in follicular lymphoma or diffuse large B-cell lymphoma. Blood. 2008;105, abstract 266.
13 O’Connor OA, Pro B, Pinter-Brown L et al. PROPEL: a multi-center phase 2 open-label study of pralatrexate (PDX) with vitamin B12 and folic acid supplementation in patients with relapsed or refractory peripheral T-cell lymphoma. Blood. 2008;112:103, Abstract 261.
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