Reflecting on 7+3
2013 marks the 40th year that the 7 + 3 protocol is the method of induction of remission for most patients with acute myelogenous leukemia.
“During the 1950s, following World War Two and after a period of civil reconstitution, a national effort, facilitated by the U.S. Congress and federal investments in the National Cancer Institute, was initiated to enhance cancer therapy in the United States. The development of mouse models of leukemia and advances in understanding the structure and function of DNA and RNA and the process of cell proliferation provided new targets for drug development and new concepts for their use.”
“But many patients with the disease still die soon after diagnosis, and patients who have more unfavorable oncogenetic subtypes, intrinsically drug resistant cells, and greater intolerance to therapy make up the vast majority of the affected and few are cured.”
In February 2013, Marshall A. Lichtman, Editor-in-Chief of Blood Cells, Molecules and Diseases, published a review of the treatment: A historical perspective on the development of the cytarabine (7 days) and daunorubicin (3 days) treatment regimen for acute myelogenous leukemia: 2013 the 40th anniversary of 7 + 3.
Here we hear from Marshall A. Lichtman about the history of the treatment, and what the future holds for people with acute myelogenous leukemia.
What is acute myelogenous leukemia?
It is a malignancy that originates in a primitive multipotential hematopoietic cell in the marrow. This process is the result of an accumulation of somatic gene mutations and epigenetic abnormalities in that cell. The abnormal cell gains a proliferative and survival advantage and forms a cellular clone that expands and, eventually, suppresses and replaces normal hematopoiesis, resulting in decreased red cells, normal white cells, and platelets. Inadequate hemoglobin levels contribute to debilitating fatigue and weakness, and the other two cytopenias result in a risk of serious infection or hemorrhage. The genetic basis for the disease is strikingly heterogeneous with many different combinations of somatic mutations.
Although acute myelogenous leukemia occurs at all ages, it increases exponentially in incidence after about age 20. Uncommon germline mutations can predispose to the disease, as does the acquired trisomy observed in Down syndrome. Chemotherapy for an unrelated cancer has become the most significant exogenous cause of the disease and is estimated to account for about 5 to 10% of cases.
How does the 7 + 3 protocol work?
The application of seven days of continuous intravenous cytarabine and a concomitant three days of intravenous daunorubicin (or a close congener), nicknamed 7+3, kills a proportion of the population of leukemic cells by damaging their DNA, which inhibits their proliferation, and by encouraging cell death (apoptosis). If a patient is susceptible to the drugs, the marrow is emptied of leukemic cells and, after a period of time, usually a few weeks, normal hematopoiesis is restored.
The principles underlying chemotherapy of acute myelogenous leukemia include: (a) the need for intensive therapy to rid the marrow of leukemic cells and (b)the coexistence of normal hematopoietic stem cells and their tolerance to chemotherapy, so that they can restore hematopoiesis after the marrow is emptied of leukemic cells. Normal, or near normal, blood counts are restored and the patient’s sense of well-being returns. This sequence of events is a remission. It is estimated that one trillion leukemic cells are present at the time of diagnosis. Remarkably, a remission can occur with a reduction to one billion residual leukemic cells, referred to as a ‘three log kill’. At this point leukemic cells are not visible in the marrow using the light microscope. The greater the reduction in leukemic cells resulting from 7+3 treatment, the longer the duration of remission, presumably.
Since 7+3 is administered, essentially, in the same way to all patients, the result of their use is determined by the type of mutations that induced the leukemia and the sensitivity of those leukemic cells, as dictated by their genotype, to therapy. Age is a good benchmark of unfavorable genetic markers, since a poor response to therapy is correlated with older age. After remission is induced, further effective therapy can be helpful to lower the number of residual leukemic cells; high doses of cytarabine have been used for this purpose. One of the great needs in therapy of acute myelogenous leukemia is finding more effective treatment after remission is induced to prevent regrowth of the residual leukemic cell population.
How was it developed?
7+3 evolved from the development of drugs that damage DNA either by a direct action such as the case of daunorubicin or by substituting fraudulent constituents of DNA during its synthesis, such as cytarabine. DNA damage was the principal approach to leukemia and, indeed, other cancer pharmacological therapy in the 1960s and early 1970s. Cytarabine came along first and showed effectiveness; daunorubicin followed, shortly thereafter, and showed effectiveness. Indeed, these two drugs were the most effective, when used individually, of those available. It was logical to combine them.
Then, the correct dose and interval for their use had to be developed through clinical trials. Initially, five days of cytarabine plus two days of daunorubicin (5+2) were tried to minimize toxic side-effects, but that approach resulted in many early relapses. The group at Roswell Park Memorial Institute, led by Jim Holland, first reported their results with 7+3, which worked much better. Their report was in the November-December 1973 issue of Cancer Chemotherapy Reports. Now 40 years later, the combination remains the backbone of treatment for most patients with acute myelogenous leukemia. Since a relatively small proportion of patients are cured, this longevity is, unfortunately, a testament to the resistance of the malignancy to improved drug therapy.
What research is currently being done to improve on this treatment?
There is a large research effort to improve our knowledge of the genetic mutations underlying the disease and of the pathogenesis of the disease, the latter focusing on acute myelogenous leukemia stem cells, the cells thought to sustain the expansion of the clone and to be responsible for recurrence in patients who relapse. The hope is that new targets will be identified that involve gene products, aberrant cell signaling pathways, and specific sensitivities of leukemia stem cells to drug action. In addition, studies of immune approaches to suppressing leukemia cells are underway, as an adjunct to drug therapy. Regenerative medicine may lead to lymphohematpoietic stem cell transplantation products that might make more patients amenable to this approach by using their own lymphohematpoietic stem cells derived from, so-called, nuclear transfer and the differentiation of their own somatic cells, such as a skin cell, into lymphohematopoietic stem cells, rather than requiring a matched donor’s stem cells, often unavailable. This approach, however, would eliminate the allogeneic immune reaction directed against the leukemic cells by donor lymphocytes, which is an important part of the effectiveness of allogeneic transplantation.
I anticipate there are ideas being incubated about which I am unaware since we now have a very much larger biomedical research establishment, extending well beyond North America, Australia, and Western Europe, the traditional bastions of medical research, into Eastern Europe, Asia, South America, and parts of Africa, and ingenious ideas are being studied in some laboratory in a far off place.
What does the future hold for acute myelogenous leukemia?
One can only hope for new insights leading to improved therapy. It is a demonic disease. Sixty percent of patients with the disease are aged 60 or older and the results of therapy for them are abysmal: few cures and little hope of a sustained remission. Even in middle aged or younger patients with favorable genotypes, the risk of a poor outcome is high. We have made incremental progress and those at younger age and with favorable genetic types of acute myelogenous leukemia benefit the most. They make up a small proportion of affected patients and, even in those categories, the treatment is harsh and the outcome uncertain. We need to do much better and, fortunately, with so many keen minds applied to the task throughout the world, I anticipate continued progress, perhaps even a great leap forward.
Cooperation among government, industry, and academic centers is an important ingredient in any future success. Governments must consider cancer, indeed, all biomedical, research as one of their most important commitments. Medical research (and other scientific research disciplines) does not have the priority it should, unless there is a military application. This fact has pernicious effects of several sorts, including inhibiting the best and the brightest from pursuing a career in cancer-research and abandoning those who have done so and are in mid-career. This failure is one of the most important problems we must reverse to assure that biomedical research is attractive to young people with high industry and intelligence. We advance only with (brash) new ideas and new paradigms and the willingness to take risks in investigating new approaches. New ideas require new, young minds entering the pipeline.