Cancer Therapy Vol 1, 63-70, 2003.
Research Article
Massimo Federico1*, Vincenzo Callea2, Romano Danesi3, Antonella Montanini1, Nicola Di Renzo4, Mario Petrini3, Mario Del Tacca3, Maria Angela Sirotti1, Giovanni Santacroce1, Alberto Bagnulo1, Matteo Dell’Olio5 and Maura Brugiatelli6 for GISL
1Dipartimento di Oncologia ed Ematologia, Università di Modena e Reggio Emilia; 2Divisione di Ematologia, Presidio Ospedali Riuniti "Bianchi, Melacrino, Morelli", Reggio Calabria; 3Divisione di Farmacologia e Chemioterapia, Dipartimento di Oncologia, Trapianti e Tecnologie Avanzate in Medicina, Università di Pisa; 4Unità Operativa di Ematologia ed Oncologia Medica, C.R.O.B., Ospedale Oncologico Regionale, Rionero in Vulture (PZ); 5Divisione di Ematologia, Centro Trapianti di Midollo Osseo, IRCCS "Casa Sollievo della Sofferenza", S. Giovanni Rotondo (FG); 6Divisione di Ematologia, Azienda Ospedaliera Papardo, Messina.
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*Correspondence to: Massimo Federico, Dipartimento di Oncologia ed Ematologia, Centro Oncologico Modenese, Università di Modena e Reggio Emilia, Policlinico - Via del Pozzo 71, 41100 Modena, Italy. Phone +39-059-4224547; Fax +39-059-4224549; e-mail: federico@unimore.it
Key words: chemotherapy, indolent NHL, MiPPeB, non-Hodgkin's lymphoma, Pentostatin
Received: 25 March 2003; Accepted: 10 April 2003; electronically published: April 2003
Contributed by Massimo Federico
Summary
Background. Taking into account the promising results achieved with purine analogs in combination regimens in patients with indolent NHL, we designed a phase II study aimed at assessing the efficacy of Pentostatin in combination with Mitoxantrone, Prednisone and Bleomycin (MiPPeB). Patients and Methods. Thirty patients (18 males and 12 females) with relapsed or unresponsive indolent NHL were treated with MiPPeB. The treatment consisted of Pentostatin 5 mg/m2, on day 1 and 8, Mitoxantrone 10 mg/m2, on day 1, Bleomycin 8 mg/m2, on day 8, Prednisone 100 mg, on day 1 and 8; cycles were administered at 3 week intervals for a maximum of 6 cycles. In 5 patients we investigated the pharmacokinetics of Pentostatin and 2’-deoxyadenosine. Results. A median of 5 cycles (range 2-6) was administered. Ten Complete Remissions (CRs) and 8 Partial Remissions (PRs) were observed, with an overall (CR+PR) response rate of 60%. The median response duration was 38 months (95% CI: 28 to 48 months). The actuarial 3-year relapse free survival for 10 patients in CR was 57%. The 3-year overall and failure free survival rates were 71% and 23%, respectively. Toxicity was mainly hematological with grade 3-4 neutropenia in 37% and grade 3 thrombocytopenia in 7% of the cases. Conclusion. MiPPeB, as used in the present study, showed a promising activity with acceptable toxicity in patients with relapsed or unresponsive indolent NHL and resulted in durable remission.
Low-grade non-Hodgkin's lymphomas (NHL) or, as they are now defined, indolent NHL (Harris et al, 1994; Harris et al, 2000), include different disease entities characterized by a similar clinical course, with a relatively long median survival and, usually, good response to initial therapy. A typical feature in the clinical course of patients with indolent NHL is their tendency to relapse, with subsequent responses of progressively shorter duration (Horning, 1993). New therapeutic approaches for indolent NHL currently under investigation include (a) attempts to eradicate the disease using high-dose chemotherapy with stem cell rescue (Schouten et al, 1994; Ladetto et al, 2002) and (b) new combinations of drugs of known specific efficacy in these diseases.
Fludarabine (2-fluoro-ara-AMP), 2-CdA (2-chlorodeoxyadenosine) and Pentostatin (2-deoxycoformicin) are new structurally similar purine nucleoside analogs (Figure 1) recently considered with increasing interest for the treatment of different lymphoproliferative disorders, including hairy cell leukemia (Chassileth et al, 1991; Ganeshaguru et al, 1991), chronic lymphocytic leukemia (Bergmann et al, 1993; Keating et al, 1998;), cutaneous T-cell lymphomas (Grever et al, 1983; Foss et al, 1994), and indolent NHL (Hoffman et al, 1994). The sensitivity of indolent NHL to purine analogs is now largely demonstrated, although the majority of studies deal with Fludarabine (Hochster et al, 1992; Redman et al, 1992) and 2-chlorodeoxyadenosine (Brugiatelli et al, 1996; Robak et al, 2001).
Figure 1: The structures of deoxyadenosine (A), and the purine analogs fludarabine (B), 2-chlorodeoxyadenosine (C), and 2'-deoxycoformycin (D).
So far, Pentostatin has been less commonly employed for the treatment of NHL (Cummings et al, 1991; Iannitto et al, 2002), although its efficacy has been well documented in other indolent lymphoproliferative disorders such as hairy cell leukemia (Grever et al, 1995), prolymphocytic leukemia (Dohner et al, 1993), Sezary Syndrome and Mycosis Fungoides (Mercieca et al, 1994). More recently a higher activity of purine analogs has been demonstrated in combination regimens (McLaughlin et al, 1994; Tobinai et al, 1995; McLaughlin et al, 1996; Flinn et al, 2000).
Considering that in patients with indolent NHL the highest therapeutic activity of purine analogs was obtained in combination regimens and, in particular, the promising results of the combination with Mitoxantrone and steroids, we designed a phase II pilot study aimed at assessing the efficacy of Pentostatin in combination with Mitoxantrone, Prednisone and Bleomycin (MiPPeB) in patients with relapsed or unresponsive indolent NHL. Bleomycin was added to the schedule in order to increase the absolute dose intensity of the regimen since this drug is characterized by very limited myelotoxicity that favors its use in combination regimens. Moreover, considering that (a) the pharmacokinetic of Pentostatin is not well described in the literature, (b) limited data are available concerning the pharmacodynamic effect of the drug, and (c) information on drug distribution would be helpful in optimizing its use in combination regimens, in 5 patients we also investigated the pharmacokinetics and pharmacodynamic effect of Pentostatin.
II. Patients and methods
Between November 1997 and July 2000, 30 patients with indolent NHL, were registered for the study and scheduled to receive 6 courses of a combination of Mitoxantrone, Prednisone, Pentostatin and Bleomycin (MiPPeB). The characteristics of these patients are summarized in Table 1. Patients were eligible for the study if they presented with a diagnosis of indolent NHL (categories A-D of the Working Formulation, or lymphocytic or follicular lymphoma of the R.E.A.L. classification), had relapsed or were unresponsive to previous therapy and presented with active disease. According to the Gruppo Italiano per lo Studio dei Linfomi (GISL) criteria (Morabito et al, 2002), active phase of the disease was defined as the presence of at least one of the following signs or symptoms: presence of systemic symptoms; bulky disease (>5 cm); anemia (Hb <10 g/L) or thrombocytopenia (Plt <100.000/L); diffuse bone marrow pattern of infiltration; lymphocyte doubling time (LDT) <12 months or a doubling of the maximum diameter of at least 3 measurable sites in less than 12 months.
Patients unresponsive to previous therapy could be included only in case of no treatment requirement for the last 6 months. Additional inclusion criteria were: age 18-75 years; stage II-IV; no more than 3 previous lines of chemotherapy; life expectancy >6 months; absence of history of repeated and/or severe infectious complications; absence of cardiac, renal, hepatic and respiratory failure; ECOG performance status 0-2; HBsAg negativity, HCV-RNA negative in HCV-Ab positive cases.
Table 1. Patient characteristics.
Characteristics No. %
Male 18 60
Female 12 40
Age
£ 60 years 18 60
>60 years 12 40
WHO performance status
0 21 70
1 8 27
2 1 3
IPI
0 - 1 15 50
2 12 40
Not assessable 3 10
Systemic
symptoms
Absent 22 73
Present 8 27
Bulky disease
No 27 90
Yes 3 10
Leukemic phase
No 26 87
Yes 4 13
Beta2-microglobulin levels
High 10 33
Normal 16 54
Not assessed 4 13
Doubling time
>12 months 17 57
<12 months 7 23
Not assessable 6 20
Previous therapy
1 9 31
2 10 33
3 11 36
Exclusion criteria included: severe or symptomatic restrictive or obstructive lung disease; ejection fraction less than 50%, signs or symptoms of congestive heart failure, or myocardial infarction within the past 3 months, angina pectoris, any major ventricular arrythmia, or uncontrolled blood pressure; active infections; concurrent or previous malignancy, other than non melanomatous skin cancer, surgically cured carcinoma in situ of the cervix, or a history of cancer that had not been active in the past 5 years; patients who were HIV positive or who had AIDS or ARC.
The present protocol was approved by the ethical committees according to the local rules and the period. It was the responsibility of the investigator to ensure that each patient gave her/his consent in writing, prior to partecipating in this study. All completed informed consent forms were retained by the investigator.
A. Treatment plan
Patients received a maximum of 6 courses of the MiPPeB regimen, given every 3 weeks, in an outpatient setting according to the following schedule: Pentostatin 5 mg/m2, on days 1 and 8, at hour 0, administered as an IV infusion in 100 ml of normal saline, over 30 minutes; Prednisone 100 mg, on days 1 and 8, at hour 0, administered as an IV infusion in 50 ml of normal saline, over 15 minutes; Mitoxantrone 10 mg/m2, on day 1, at hour 6, administered as an IV infusion in 100 ml of normal saline, over 30 minutes; Bleomycin 8 mg/m2, on day 8, at hour 4, administered as an IV infusion in 100 ml of normal saline, over 15 minutes (Figure 2).
The MiPPeB courses were given at 21-day intervals, provided that at the time of recycling WBC count was >4.0 x 109/L, and platelet count >100 x 109/L. If the above-mentioned criteria were not satisfied on the day of recycling, the administration of a subsequent MiPPeB course was performed according to the dose modifications rules reported in Table 2.
Figure 2. Treatment plan.
Table 2. Dose modifications.
WBC PLT DOSES DRUGS
>4.0 >100 100% All
3.9 - 3.0 99 - 75 100% Bleomycin
50% Mitoxantrone, Pentostatin
<3.0 <75 100% Bleomycin
0% Mitoxantrone, Pentostatin
B. Response assessment
Response to treatment was assessed within four weeks after the end of the last chemotherapy. At this time, a CT-scan of the chest and abdomen/pelvis was performed together with any other instrumental investigation found to be abnormal at any previous evaluation. Complete remission (CR) was defined as the disappearance of all clinical evidence of disease and the normalization of all laboratory values and radiographs abnormal before starting treatment. Patients who achieved CR during therapy, but relapsed within 30 days after therapy had been completed, were classified as non responders. Partial remission (PR) was defined as a greater than 50% reduction in the largest dimension of each anatomic site of measurable disease for at least one month. No remission (NR) was defined as a less than 50% regression or stable or progressive disease. All early deaths due to disease progression or treatment-related toxicity were considered as treatment failure, and included in the group of NR.
Patients were considered evaluable for response assessment after at least 3 courses, unless treatment was discontinued because of disease progression or early death. Toxicity was assessed according to the WHO criteria. It was the responsibility of the clinical investigators to ensure that all clinical record forms designed for the study were completed satisfactorily and returned to the trial office. The clinical investigator was required to sign each completed record form to signify that it represented an accurate record of the patient.
C. Statistical analysis
This was a prospective, open label, multicenter, phase II pilot study to assess the feasibility, safety, tolerability and efficacy of a Pentostatin-based regimen in patients with relapsed indolent NHL. The sample size was small and no statistical hypothesis testing was planned. The trial size was based on feasibility and was chosen for practical rather than statistical considerations in order to obtain information for planning a possible phase III study.
Main endpoints were: complete remission, duration of remission, disease free survival. Secondary endpoint was overall survival. All data were analyzed with the Statistical Package for the Social Sciences (SPSS), release 9.0.1. Differences in CR rates between the groups were analyzed by the Pearson’s C2 test for contingency tables. Overall survival (OS), disease free survival (DFS) and relapse free survival (RFS) curves were estimated by the method of Kaplan-Meier. Overall survival was calculated from the beginning of treatment until death from any cause. DFS and RFS were calculated from the end of induction therapy to the first evidence of disease. Response rates, survival, relapse and toxicity were analyzed on all patients. A p value of 0.05 (two-sided) was considered the limit of significance for all the analyses.
D. Pharmacokinetic/pharmacodynamic study of Pentostatin
In addition to the clinical trial, 5 of the 30 patients were enrolled in a pharmacokinetic/pharmacodynamic study of Pentostatin.
Heparinized plasma samples were obtained at baseline (before the administration of Pentostatin) and at 5, 15, 30, 60 min, 2, 3, 6, 12, 18, 24, 48, and 72 hours after drug dose in five patients, three on day 1 and two on day 8 of treatment. Plasma concentrations of Pentostatin (Danesi et al, 2002) and 2’-deoxyadenosine (Koller et al, 1980) were assessed by specific high-performance liquid chromatography (HPLC) methods with ultraviolet detection. Intra- and inter-assay precision (coefficients of variation) were <10.1% for Pentostatin and <9.4% for 2’-deoxyadenosine. Individual plasma concentration vs. time data were fitted using non-linear least-squares regression analysis by means of computer software (MWPHARM, MediWare, Groeningen, the Netherlands) and peak plasma concentration, terminal half life, total body clearance and apparent volume of distribution at steady state were calculated by conventional methods (Rowland and Tozer, 1995).
III. Results
Between November 1997 and July 2000, 30 patients were registered for the study and all were assessable for response and toxicity.
The median age was 57 years (range 36 - 72), with 18 patients younger than 60 years. Among the remaining clinical features at presentation, it should be noted that 76% had advanced (stage III or IV) disease, 13 (43%) had non follicular histology, and 5 (17%) had the involvement of two extranodal sites. In addition, 20% presented with systemic symptoms and 23% had LDH over the normal range. Six patients were refractory to previous therapy, 12 had a duration of CR lasting less than 12 months and 12 relapsed after more than one year of CR.
At study entry 9 patients had relapsed after first line therapy, and 21 had received two or more chemotherapy regimens before MiPPeB. Seven patients had already received a purine analog (Fludarabine), in 6 cases combined with an anthracycline which in 4 of those cases, consisted of Mitoxantrone. Finally, one patient was in relapse after high dose therapy with stem cell rescue. Median time between initial diagnosis and inclusion in the present study was 46 months (range 10-110 months). The disease history lasted less than one year, 1-3 years, and more than 3 years in 6, 12 and 12 patients respectively. The mean interval between last therapy and study entry was 18 months (range 4-46 months); this interval was less than one year in 12 patients (40%), and more than one year in the remaining 18 cases. A total of 152 courses were administered to the 30 patients. The median number of cycles was 5 (range 2 to 6) and the median interval between cycles was 26 days (range 19 to 70). Twenty-eight patients completed at least 3 courses and 18 received all the 6 planned courses. Reasons for early withdrawal and status at that time are summarized in Figure 3. The main reason for interrupting planned therapy was progressive disease (6 patients) or unsatisfactory response (3 patients). However, four patients stopped therapy while in CR after 3, 4, 5, 5 courses, respectively, because of poor patient compliance.
Figure 3. Flow-chart of the study.
A. Response
With MiPPeB, 10 patients (33%) (95% CI: 16% to 50%) achieved a CR and an additional 8 patients (27%) (95% CI: 11% to 43%) a PR, with an overall response rate of 60% (95% CI: 43% to 76%). In addition, 7 (23%) (95% CI: 8% to 39%) cases showed a durable stable phase of the disease after treatment. The objective response rate was similar for patients with early or late relapse (p=0.247), and for those with one or more previous therapies (p=0.602). After a median follow-up of 30 months (39 months for patients still alive) 6 patients out of 10 in CR relapsed. The 3-year RFS is 57% (95% CI: 27 to 52) (Figure 4). The median duration of remission for 18 responding patients was 38 months (range 2 - 57), better than the median duration of the last response (21 months, range 6-36 months). Nine patients died, all of them because of disease progression. The 3-year survival rate for the 30 enrolled patients is 71% (Figure 5).
Figure 4. Kaplan Meier Relapse-free survival.
Figure 5. Kaplan Meier Overall survival.
Among baseline patients’ characteristics of potential prognostic value only a short doubling time was associated with a significantly lower chance of achieving a response to MiPPeB therapy (P=0.047). Moreover, performance status (P=0.0192), number of previous therapies (0.0001), and beta2-microglobulin (0.0174), resulted of prognostic relevance in univariate analysis of survival. Given the limited number of cases a multivariate analysis was not performed.
B. Toxicity
Toxicity was rather mild, especially considering that the majority of cases were heavily pretreated. No significant organ toxicity was reported. As expected in a pretreated patient setting, toxicity was mainly hematological consisting of frequent although not severe leucopenia and in few instances thrombocytopenia. Leucopenia was not associated with severe infection occurrence.
C. Pentostatin pharmacokinetic /pharmacodynamic study
Mean peak plasma concentrations of Pentostatin and 2’-deoxyadenosine were 7±2.6 m M and 68±23 m M, respectively, while mean baseline 2’-deoxyadenosine levels were 4.1±1.9 m M. Plasma concentration-time curves showed a first-order elimination with biphasic decay, with a terminal half life of Pentostatin of 8.7±3.1 hours. Average total body clearance (CLTB) of Pentostatin was 103.45±22.4 mL/min and apparent volume of distribution at steady state (Vdss) was 42.4±7.
V. Discussion
One of the main features of the clinical course of indolent lymphomas is represented by its continuous pattern of relapse with subsequent responses of shorter and shorter duration after conventional chemotherapy (Horning SJ, 1993). So far, this clinical behavior has not been changed by the introduction of purine analogs and immunotherapy with monoclonal antibodies. Some more durable responses have been reported after high dose chemotherapy with stem cell rescue (Schouten et al, 1994; Ladetto et al, 2002) although this treatment approach cannot be used in the vast majority of cases.
Therefore, keeping in mind this unavoidable tendency to relapse, it would be advisable to design a long-term treatment program for each patient by choosing among the different treatments now available for this histological category.
Therefore, the present study introduces the combination of Pentostatin with Mitoxantrone and Bleomycin among the effective therapeutic options suitable for patients with advanced indolent lymphomas.
Previously, the activity of purine analogs as single agents has been clearly demonstrated. In patients with relapsed or recurrent indolent NHL the response rate to Fludarabine ranges between 43% and 70% (Hochster et al, 1992; Hoffman et al, 1994).
Similar results have been reported for 2-CdA. In a group of 14 patients unresponsive to previous treatments, 3 CR and 4 PR have been reported by Brugiatelli et al. (1996) in a multicentric study. In a preliminary study of 26 patients with untreated indolent NHL Emanuele et al (1994) reported 35% and 54% CR and PR respectively.
As far as Pentostatin is concerned an overall response rate of 29% and 33% has been reported in patients with relapsed or refractory indolent NHL by Cummings et al (1991), and Duggan et al (1990), respectively. These two studies using Pentostatin as salvage treatment demonstrate the possibility of obtaining clinical responses, up to more than 50 months in patients with NHL.
The higher efficacy of Fludarabine in combination with Mitoxantrone as compared with its use as single agent has been repeatedly reported with response rates up to 90%, when used as first line and salvage treatment respectively (McLaughlin et al, 1994; Seymour et al, 2001). Using Fludarabine, Mitoxantrone and Dexamethasone (FND), McLaughlin et al (1996) achieved an overall response rate of 94% (47% CR and 47% PR) in a group of 51 patients with recurrent or refractory indolent NHL.
Although all purine analogs could exert similar effectiveness, so far, the clinical experience with 2-CDA and Pentostatin for the treatment of lymphomas (Cummings et al, 1991; Brugiatelli et al, 1996; Iannitto et al, 2002) is much more limited as compared to Fludarabine. At the moment their use is almost completely confined to the treatment of hairy cell leukemia (Grever et al, 1995) and in the case of Pentostatin of T-cell neoplastic diseases as a single agent (Mercieca et al, 1994). More recently, the combination of Pentostatin with Cyclophosphamide or Chlorambucil has been reported with promising results (Goodman, 2000; Waselenko et al, 2000; Weiss, 2000).
Based on the known efficacy of the combination of Fludarabine and Mitoxantrone and on in vitro data of synergism of the latter one with Pentostatin (Morabito et al, 1997), we designed the present MiPPeB schedule in order to take advantage of the synergistic effect of the two drugs, possibly potentiated by the addition of a third non-myelotoxic drug, namely Bleomycin. In addition, we tried to maximize the synergistic effect of the combination by using a time-dependent scheme of administration which could respect the biological properties of the different drugs, similar to the schedules employed for the treatment of acute leukemias.
The results of the present study performed on heavily pretreated patients show that MiPPeB combination chemotherapy induced an overall response rate of 60% with 33% CR, thus at least comparable to the results obtained with the combination of Fludarabine and Cyclophosphamide (Flinn et al, 2000) or Fludarabine and Mitoxantrone (McLaughlin et al, 1994; McLaughlin et al, 1996; Seymour et al, 2001).
The efficacy of this combination is confirmed by the duration of response which is similar that obtained in our patients by the previous treatment. It is noteworthy that out of 7 cases already treated with Fludarabine mostly in combination with Mitoxantrone 2 CR were obtained and 2 cases reached a stable disease status, thus suggesting the possibility of effectively using both purine analogs during the course of the disease.
Moreover, the toxicity profile of the MiPPeB schedule deserves a comment. The main side effect was myelotoxocity, but, despite frequent episode of neutropenia, purine analog-induced immunedepression and heavy pretreatment, often including another purine analog, infectious complications were not frequent and never severe. Only one death due to infection occurred in a patient with disease progression.
Finally, the pharmacokinetic and pharmacodynamic studies demonstrated that at the present dosing schedule, Pentostatin reaches effective ADA inhibitory levels in plasma, as shown by the increase in 2’-deoxyadenosine concentrations over baseline levels; in addition to this, the Vdss value lower than total body water indicates that extensive tissue binding does not occur, while the extent of drug clearance suggests that the kidney is the main route of drug excretion from the body, as confirmed by a recent study in patients with mild renal impairment (Lathia et al, 2002).
In conclusion, the results of the present study demonstrate the efficacy with acceptable toxicity of Pentostatin included in combination chemotherapy for the salvage treatment of indolent lymphomas not suitable for high dose chemotherapy approaches. Accordingly, MiPPeB or MiPPeB-like schedules deserve inclusion among the conventional chemotherapy options for this category of lymphoproliferative disorders and should be tested also in a front-line setting.
Acknowledgments
The study was supported by Associazione Angela Serra per la Ricerca sul Cancro, Modena, and Fondazione Ferrata-Storti, Pavia, Italy.
Participating institutions
Gruppo Italiano per lo Studio dei Linfomi (GISL) - Chairpersons: M. Federico, P. G. Gobbi, L. Baldini.
List of Institutions contributing to the present study:
Dipartimento di Ematologia e Trasfusionale (F. Nobile), Presidio Ospedali Riuniti "Bianchi, Melacrino, Morelli", Reggio Calabria; Cattedra e Servizio di Ematologia (A. T. Maiolo, L. Baldini), IRCCS Ospedale Maggiore, Milano; Dipartimento di Oncologia ed Ematologia (G. Torelli, M. Federico, S. Sacchi), Università di Modena e Reggio Emilia, Modena; Divisione di Medicina (G. Partesotti, G. Santacroce), Ospedale Civile, Sassuolo, Modena; Divisione di Medicina (A. Bagnulo, A. Zoboli), Ospedale S. Sebastiano, Correggio, Reggio Emilia; Divisione di Ematologia (A.M. Carella, N. Di Renzo, M. Dell’Olio), IRCCS "Casa Sollievo della Sofferenza", S. Giovanni Rotondo, Foggia; Dipartimento di Oncologia (M. Petrini, F. Caracciolo), Divisioni di Ematologia e Farmacologia, Università di Pisa; Unità Operativa di Oncologia Medica (V. Pitini), Policlinico Universitario, Messina.
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