26
M. R. Grever
effective in achieving responses to establish a safe dose and schedule for subsequent trials. Based upon these observations, we also pursued
the use of pentostatin in patients with hairy cell leukemia [9]. We found that this agent was capable of inducing prolonged complete remissions in more than 75% of patients with hairy cell leukemia [10,11]. This agent was well tolerated and repre- sented a major therapeutic breakthrough in treating this disease. In addition, others also found that pentostatin was extremely effective in inducing very durable complete remissions [12–14]. This agent was usually administered in the outpatient clinic on an every-other-week schedule. The usual dose at The Ohio State University was 4 mg/m2 adminis- tered intravenously every 2 weeks. Some titration of the dose and schedule were utilized to reduce myelosuppression initially in treating these patients with a very compromised bone marrow reserve. Other investigators utilized alternative doses and schedules. While pentostatin was the first purine analog used
to effectively treat hairy cell leukemia, another very effective agent (cladribine) was introduced in 1990 [15]. Cladribine produced very durable remissions in more than 90% of these cases [16]. In contrast to pentostatin being administered in multiple out- patient doses, cladribine was initially delivered as a 7-day continuous intravenous infusion. Initially, patients with an active infection were not enrolled on cladribine trials because this agent could produce prolonged myelosuppression [15]. The ease of drug administration resulted in this agent being the more commonly used purine nucleoside analog for initial therapy of hairy cell leukemia [18]. Both of these purine analogs substantially contributed to the successful development of a therapeutic strategy that improved the outcome for these patients. Over the past two decades, alternative schedules and routes of cladribine administration have been explored in an effort to reduce myelosuppression and to facilitate administration [19–21]. Some hematologists administer cladribine over 5 days, weekly for up to 6 weeks, or subcutaneously. There is no conclusive proof that these alternative routes of cladribine administration are better than the initial regimen delivered over 7 days. However, the long- term results with the 7-day continuous intravenous infusion have longer follow-up than these alternative approaches [22]. Despite the high percentage of patients achieving
a complete remission, about 30–40% of patients will eventually relapse following either pentostatin or cladribine [22]. Patients who have achieved a complete hematologic remission based upon
recovery of normal peripheral blood counts and morphologic examination of the bone marrow show residual leukemia in about half of the patients. The percentage of cases with minimal residual disease depends upon the method utilized and the timing of the bone marrow examination. The propensity for relapse may be related to the extent of residual disease shown by either specialized immunohisto- chemical stains or flow cytometry focusing upon the characteristic profile of a monoclonal B cell popula- tion expressing CD11c, CD103, CD25, and CD123 [23]. The utility of using the extent of minimal residual disease to predict relapse needs further study to refine and validate the exact relationship. In comparing multiple trials with long-term
clinical follow-up, it is clear that the introduction of the purine nucleoside analogs changed the natural history of this disease. Both pentostatin and cladri- bine have contributed to a high number of patients who have achieved durable complete remissions, and will likely have a survival benefit based upon these responses. Both agents appear equivalent. The estimated disease-free survival at 10 years is approxi- mately 68% in those treated with pentostatin [24]. In a separate trial reported by Else et al., the follow- up at 15 years following pentostatin showed that 47% of the patients relapsed [25]. Else’s study with cladribine showed that 48% of patients relapsed at 9 years of follow-up [25]. Each of these reports compares favorably with the projected survival observed in 1984 as stated above. The conclusion that both agents are equally effective appears sound in the absence of a prospec- tively randomized clinical trial that is unlikely to be successfully conducted in this rare leukemia [22]. Patients treated with cladribine appear to have more episodes of febrile neutropenia, and this agent is often not utilized in patients with an ongoing infection. In contrast, pentostatin may be less myelosuppressive in the early phase of therapy [12]. Pentostatin delivered on an intermittent schedule may be dose- and schedule-modified to avoid severe and prolonged myelosuppression. Both agents are effective and can be delivered on an outpatient basis. Since neither purine analog can cure this disease as
monotherapy, there are opportunities for further exploration of other novel agents and combinations that may be effective in achieving responses in patients who have relapsed shortly after the initial therapy. The model that was initially utilized to identify the potential value of purine analogs in treating patients with chronic B cell leukemias was based upon the impact of these agents on malignant B cell survival. Furthermore, identification of
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