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Individualizing Therapy for the Hematologic Malignancies: The Stuff of Genes and Dreams

Lombardi Comprehensive Cancer Center, Washington, DC

When I first entered this field more than 30 years ago, a hematology text (oncology was not yet a discipline) would include a lone chapter on malignant disorders, with sections on leukemia, lymphoma, and myeloma. It featured morphology and clinical descriptions of the various subtypes, which often had names that, in many cases, bore no relationship to their cell of origin (eg, reticulum cell sarcoma, which is neither derived from a reticulum cell nor is it a sarcoma, but is non-Hodgkin's lymphoma). There were no effective therapies and, as a consequence, similar outcomes were reported among patients with each disease entity, masking any important biologic differences. Several editions later, the single chapter became three. Next, one leukemia chapter became one each for the acute and chronic, then a lymphoid and a myeloid, and the lymphomas into Hodgkin's and non-Hodgkin's.

Improvements in therapies led to the pivotal observation that, despite morphologic similarities, there was marked clinical heterogeneity: a uniform treatment regimen induced responses in some patients who would do extremely well, whereas others progressed rapidly and died from their disease, with no clear explanation for the discrepancy. The identification of the first clonal karyotypic abnormalities in a malignant disorder, the Philadelphia chromosome in chronic myelogeneous leukemia, led to a search for other genetic lesions with clinical relevance.¹ Once the various immunologic subtypes of lymphocytes were apparent, new classification schemes followed naturally. The clinically based International Working Formulation² with its low-, intermediate- and high-grade lymphomas, some in the incorrect category, was replaced by the WHO scheme, which uses immunology, genetics and clinical features to categorize more than 30 unique types of lymphomas³; whereas an increased understanding of the importance of molecular and genetic abnormalities has relegated the French American British (FAB) Classification to the ghost of leukemia past.⁴ Be assured that newer classifications will be created in the not too distant future.

In a recent editorial in the Journal of Clinical Oncology, Sandra Horning, MD, Daniel G. Haller, MD, and I described the improving status of hematologic malignancies in the Journal, focusing on the shortened review process and time to subsequent publication, with an increasing number of high-quality papers.⁵ In a recent letter circulated to the ASCO membership by our current president, Sandra Horning, we are again reminded that the Society considers those of us who care for and/or conduct research related to patients in the field of leukemias, lymphomas, and myeloma to be valued members. A greater number of sessions at the Annual Meeting will be devoted to these diseases, with better representation of hematologic oncologists on ASCO committees, and a number of new task forces on academic oncology, translational research, biomarkers and imaging, and survivorship.

All of that is well and good if there is substance to back it up. The present supplement clearly demonstrates that there is. My colleagues Sandra Horning, Hartmut Doehner, MD, and Ken Anderson, MD, have assembled a group of internationally recognized investigators who have made important contributions to our understanding of the biology and genetics of hematologic malignancies and to the therapies for these patients. Indeed, many of our current concepts of tumor biology and immunology that apply to solid tumors emerged from the study of hematologic disorders. The unifying theme in this supplement is the inter-relationship between molecular pathogenesis, classification, and therapy.

What is apparent is that various patients with a similar histology have different responses to the same treatment because they, in fact, have different diseases at the molecular and genetic level. Gene expression profiling provides clues for the clinical diversity first of diffuse large B-cell lymphoma and now other histologies of NHL, as well as leukemias and myeloma.⁶ Such assays also suggest distinct strategies and potential novel therapeutic targets.

Thus, in time, tumors will no longer be classified on the basis of their morphologic appearance and immunophenotype, but by their abnormal gene expression profile, aberrant signaling or enzymatic pathway, receptor, or other biologic abnormality instead, because of the potential therapeutic relevance. Indeed, in the current study in the Cancer and Leukemia Group B (CALGB) for patients with previously untreated diffuse large B-cell non-Hodgkin's lymphoma the clinical comparison of the bolus R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) regimen to infusional R-EPOCH (R-CHOP plus etoposide) is secondary to the information from DNA microarrays on biopsy specimens from each of the patients. This prospective evaluation may identify which patients are better treated with a particular therapeutic approach.

For decades, chemotherapy regimens appeared to be developed as if using letters in a game of Scrabble (Mattel Inc, El Segundo, CA), resulting in acronyms without improvement in patient outcome. We are in a different era in which novel therapeutic strategies are increasingly based on biology, genetics, and immunology. A major advance from therapies of the past is the increasing importance of noncytotoxic agents. At the extreme are the marginal zone lymphomas, many of which develop in association with an infectious organism and a remission of the lymphoma can be attained by eradicating the pathogen.⁷ The immunomodulatory agents and proteasome inhibitors have altered the treatment paradigm for patients with multiple myeloma.^8,9 Dexamethasone and thalidomide has replaced melphalan and prednisone, or VAD (vincristine, doxorubicin, and dexamethasone) as the initial treatment of multiple myeloma. All-trans-retinoic acid in acute promyelocytic leukemia,¹⁰ and imatinib in chronic myelogenous leukemia¹¹ have made other approaches obsolete. Monoclonal antibodies, radioimmunotherapeutics, anti-idiotype vaccines, and antisense molecules have refocused the clinical trials in patients with lymphoid malignancies. Indeed, CALGB investigators have abandoned chemotherapy as the initial therapy of patients with follicular lymphoma and are using combinations of biologic agents instead.

The articles in this issue promise a future in which patient specific therapies applied to biologically distinct diseases will improve survival. To ensure that this goal will be realized requires a dedication not only to enhance accrual to clinical trials, but to the collection and storage of tissue whenever possible for correlative science in each current clinical study, and for future investigations to continue the progress in the hematologic malignancies.

Author's Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Nowell PC, Hungerford DA: Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 25:85-109, 1960

2. The Non-Hodgkin‘s Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of Non-Hodgkin’s lymphomas. Cancer 449:2112-2135, 1982

3. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the clinical advisory committee meeting—Airlie House, Virginia. J Clin Oncol 17:3835-3849, 1999[Abstract/Free Full Text]

4. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukaemias: French-American-British (FAB) co-operative group. Br J Haematol 33:451-458, 1976[Medline]

5. Cheson BD, Haller D, Horning SJ: Serving interests in hematologic malignancies in the Journal of Clinical Oncology. J Clin Oncol 23:3666-3667, 2005[Free Full Text]

6. Rosenwald A, Wright G, Chan WC, et al: The use of molecular profiling to predict survival after chemotherapy for large B-cell lymphoma. N Engl J Med 346:1937-1947, 2002[Abstract/Free Full Text]

7. Wotherspoon AC, Doglioni C, Diss TC, et al: Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342:575-577, 1993[CrossRef][Medline]

8. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999[Abstract/Free Full Text]

9. Richardson P, Sonneveld P, Schuster MW, et al: Bortezomib vs. dexamethasone in relapsed multiple myeloma: A phase 3 randomized study. Proc Am Soc Clin Oncol 23:558, 2004 (abstr 6511)

10. Chomienne C, Balitrand N, Ballerini P, et al: All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells. J Clin Invest 88:2150-2154, 1991

11. Kantarjian H, Sawyers C, Hochhaus A, et al: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645-652, 2002[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cheson, B. D. Search for Related Content PubMed PubMed Citation Articles by Cheson, B. D. Social Bookmarking                            What's this?