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Journal of Clinical Oncology, Vol 19, Issue 23 (December), 2001: 4351-4353
© 2001 American Society for Clinical Oncology

SPECIAL DEPARTMENTS

Cd40 Ligand Therapy of Lymphoma Patients

Anas Younes

University of Texas M.D. Anderson Cancer Center, Houston, TX

To the Editor:Vonderheide et al1 reported their experience with recombinant human CD40 ligand (CD40L) in cancer patients. In that phase I study, nine patients with non-Hodgkin’s lymphoma (NHL) were included. The authors reported that one patient with NHL had a transient partial remission. Because of the controversy surrounding the role of CD40 ligand in B-cell lymphoid tumors,2 it would be important that the authors provide detailed information on all nine lymphoma patients enrolled on this study.

We and others have reported that soluble CD40L may enhance the survival of freshly isolated malignant B cells and in some cases may enhance the proliferation of these cells in vitro.3-8 This effect has been attributed to the activation of NF-{kappa}B and upregulation of Bcl-XL and cFLIP.5,7,9 Furthermore, gene transfer of CD40L has been reported to cause thymic lymphoproliferative disorders and T-cell lymphoid malignancies in mice.10 Therefore, it is interesting to learn that one lymphoma patient has indeed responded to soluble CD40L. However, the following information should also be provided to get the entire picture:

1. What are the exact histologic types according to the Revised European-American Lymphoma classification of all nine lymphoma patients? What are the characteristics of the lymphoma patient who responded? Where are the sites of disease in this patient and what sites responded to CD40L? Because this patient eventually experienced disease progression, did the disease progress at a faster pace than expected?
2. The remaining eight patients who did not respond: did they have stable disease or progression of disease? Was there any evidence of accelerated growth? Were they treated with chemotherapy at the time of progression and what was the response to chemotherapy?
3. Did the investigators determine pretreatment soluble CD40L levels in patients’ sera?

Providing this information would be greatly appreciated by investigators who are interested in further evaluating the CD40L pathway for the treatment of B-cell NHL.

REFERENCES

1. Vonderheide RH, Dutcher JP, Anderson JE, et al: Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol 19: 3280-3287, 2001[Abstract/Free Full Text]

2. Fiumara P, Younes A: CD40 ligand (CD154) and tumour-necrosis factor-related apoptosis inducing ligand (Apo-2L) in haematological malignancies. Br J Haematol 113: 265-274, 2001[Medline]

3. Clodi K, Asgary Z, Zhao S, et al: Coexpression of CD40 and Cd40 ligand in B-cell lymphoma cells. Br J Haematol 103: 270-275, 1998[Medline]

4. Clodi K, Snell V, Zhao S, et al: Unbalanced expression of Fas and CD40 in mantle cell lymphoma. Br J Haematol 103: 217-219, 1998[Medline]

5. Younes A, Snell V, Consoli U, et al: Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic lymphoma. Br J Haematol 100: 135-141, 1998[Medline]

6. Voorzanger-Rousselot N, Favrot M, Blay Jy: Resistance to cytotoxic chemotherapy induced by CD40 ligand in lymphoma cells. Blood 92: 3381-3387, 1998[Abstract/Free Full Text]

7. Kitada S, Zapata JM, Andreeff M, et al: Bryostatin and CD40-ligand enhance apoptosis resistance and induce expression of cell survival genes in B-cell chronic lymphocytic leukaemia. Br J Haematol 106: 995-1004,

8. Castillo R, Mascarenhas J, Telford W, et al: Proliferative response of mantle cell lymphoma cells stimulated by CD40 ligation and IL-4. Leukemia 14: 292-298, 2000[Medline]

9. Furman RR, Asgary Z, Mascarenhas JO, et al: Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. J Immunol 164: 2200-2206, 2000[Abstract/Free Full Text]

10. Brown MP, Topham DJ, Sangster MY, et al: Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nat Med 4: 1253-1260, 1998[Medline]

Response

Robert H. Vonderheide, Janice P. Dutcher, Jeanne E. Anderson, S. Gail Eckhardt, Dania A. Caron, John G. Gribben

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
New York Medical College, Our Lady of Mercy Cancer Center, Bronx, NY
Institute for Drug Development, San Antonio, TX
Immunex Corporation, Seattle, WA
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

In Reply:Dr Younes raises several interesting questions regarding our phase I study of recombinant human CD40 ligand (rhuCD40L) in cancer patients.1 Table 1 outlines further information regarding the nine patients with non-Hodgkin’s lymphoma (NHL) treated with this agent.


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  		Table 1.  Further Clinical Data for Nine NHL Patients Treated With rhuCD40L
 
The patient with a partial response was a 52-year-old woman with large-cell immunoblastic T-cell lymphoma who at study entry had progressive disease (multiple skin lesions and lymphadenopathy). She had previously received chemotherapy, radiation therapy, and cytokine therapy with varying clinical responses, including prior partial responses and one complete response to radiation therapy. One month before study entry, she had progressive disease despite 2-deoxycoformycin. After the first course of rhuCD40L, the patient achieved a partial response, as evidenced by regression of skin lesions and reduced lymphadenopathy. After receiving a second course of rhuCD40L, the patient developed tiny, new skin lesions and a bone marrow biopsy showed relapse of her T-cell NHL. The patient was subsequently treated with chemotherapy but had died by the time of the 9-month poststudy follow-up. Tumor cell CD40 expression was not evaluated in this patient. Among the other NHL patients, six of eight patients had progressive disease after a single course of rhuCD40L, and two patients (nos. 2051 and 2553, Table 1) had stable disease after one course but progressive disease after two courses. Serum CD40L levels were not measured.

Overall, we believe the data do not suggest that treatment of NHL patients with rhCD40L at this schedule resulted in acceleration of progressive disease.

REFERENCES

1. Vonderheide RH, Dutcher JP, Anderson JE, et al: Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol 19: 3280-3287, 2001




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