Lomustine (chloroethylnitrosourea [CCNU]), ifosfamide, bleomycin, vincristine, and cisplatin (CIBO-P) is an effective regimen for patients with poor prognostic refractory or multiple disease recurrent aggressive non-Hodgkin lymphoma

Authors


Abstract

BACKGROUND

The current study was designed to assess the activity and safety of a novel combination therapy for patients with recurrent or refractory aggressive non-Hodgkin lymphoma (NHL).

METHODS

Forty-three consecutive patients with recurrent or refractory aggressive NHL were treated with lomustine (chloroethylnitrosourea [CCNU]; 60 mg/m2 on Day 1), ifosfamide (1.5 g/m2 on Days 1, 2 and 21, 22), bleomycin (5 mg/m2 on Days 1, 5 and 21, 25), vincristine (1.4 mg/m2 on Days 1, 8 and 21, 28), and cisplatin (25 mg/m2 on Days 3, 4, 5 and 23, 24, 25), every 42 days (CIBO-P regimen).

RESULTS

Thirty-nine patients (91%) were evaluable for response. The median patient age was 63 years. Thirty-five percent of the patients had received ≥ 2 lines of previous chemotherapy and 40% had elevated lactate dehydrogenase levels at the time of treatment initiation. The overall objective response rate was 77% (95% confidence interval [95% CI], 63–90%), including 19 (49%) complete (CR) and 11 (28%) partial responses. CIBO-P induced responses in primary refractory disease and in patients treated for second or subsequent disease recurrences. A CR with previous therapy was the most important factor associated with a significantly higher CR rate. The median duration of response was 6 months (95% CI, 4.4–7.7 months) and the median survival duration was 10.7 months (95% CI, 5.9–18.1 months). Five patients (11.6%) remained disease free for ≥ 24 months. By multivariate analysis, a CR with previous therapy and average dose intensity of CIBO-P drugs were independent prognostic factors for time-to-treatment failure, whereas a CR with previous therapy and serum lactate dehydrogenase were independent predictors for survival. Myelosuppression was the most frequent serious complication of this regimen. However, none of the patients had hemorrhage with thrombocytopenia, and only 2 patients (5%) had febrile neutropenia.

CONCLUSIONS

In the current study, CIBO-P was a novel, highly active, and safe combination therapy for patients with refractory disease with a poor prognosis or for patients with multiply recurrent aggressive NHL. Cancer 2005. © 2005 American Cancer Society.

Intermediate and high-grade non-Hodgkin lymphoma (NHL) are commonly treated with anthracycline-containing regimens such as CHOP (cyclophosphamide, hydroxydaunomycin, oncovin, prednisone),1 but 50–60% of patients will fail to obtain a complete response (CR) with first-line therapy (primary refractory NHL) or will have disease recurrence after achieving a CR (recurrent NHL).

Platinum-based chemotherapy has been used extensively as salvage therapy for NHL. DHAP (dexamethasone, cytosine arabinoside [ara-C], and cisplatin) and ESHAP (etoposide, methylprednisolone, ara-C, and cisplatin) are two commonly used regimens.2, 3 They have proven to be effective, non–cross-resistant regimens, particularly for patients with NHL who have favorable prognostic characteristics. Ifosfamide has also been used widely in the treatment of patients with refractory lymphoma.4–6 EPIC (etoposide, prednisolone, ifosfamide, and cisplatin) was found to be an effective low-toxicity salvage regimen for NHL.7

For patients with recurrent or refractory aggressive NHL, one therapeutic approach is to incorporate other non–cross-resistant agents to improve existing combination regimens. Lomustine (chloroethylnitrosourea [CCNU]) is a nitrosourea with proven activity in hematologic and solid tumors. It is lipid soluble and easily enters the brain. Alkylation and carbamoylation by lomustine metabolites interfere with the synthesis and function of DNA, RNA, and proteins. CCNU has been tested in a number of Phase II studies as a single agent or in combination chemotherapy in both Hodgkin disease and NHL. CCNU-based regimens for patients with recurrent or refractory aggressive NHL seem at least as effective as most other regimens utilized in salvage treatment of NHL, with a very acceptable toxicity.8–10

Preclinical studies have demonstrated synergisms between ifosfamide and CCNU, and between cisplatin and CCNU.11, 12 The combined action of the antitumor, antibiotic bleomycin and CCNU has been studied in human lymphocytes in vitro. At late G1 and G2 states of the cell cycle, the combined treatment leads to a significant increase in both the percentage of aberrant cells and production of dicentrics and rings.13 The combinations of 1) ifosfamide, bleomycin, and vincristine, 2) CCNU and bleomycin, and 3) CCNU, bleomycin, and cisplatin have been tested in hematologic and solid tumors with very mild nonhematologic toxicity and moderate hematologic toxicity.14–16

The novel combination chemotherapy with CCNU, ifosfamide, bleomycin, vincristine, and cisplatin (CIBO-P) comprises myelosuppressive (CCNU, ifosfamide, and cisplatin) and nonmyelosuppressive (vincristine and bleomycin) drugs with proven activity in NHL. Their potential antitumor synergy, nonoverlapping toxicity profiles, and lack of cross-resistance make this combination an attractive salvage regimen.

The objectives of the current study were to assess the activity and safety of CIBO-P in patients with recurrent or refractory aggressive NHL, evaluate the long-term results, and identify prognostic factors in the study cohort.

MATERIALS AND METHODS

The study was carried out by the Medical Oncology Unit of the University Hospital of Parma (Parma, Italy) under the auspices of the Italian Oncology Group for Clinical Research. The protocol was approved by the institutional ethics committee. Signed, written informed consent was obtained from each patient.

Patient Selection and Evaluation

Eligibility criteria were as follows: men or women > 18 years; histologically proven diagnosis of aggressive NHL (previous diagnoses were reformulated according to the World Health Organization [WHO] classification of lymphoid neoplasms17); documented disease recurrence after previous chemotherapy or resistant disease to previous chemotherapy; measurable or evaluable disease; WHO performance status of 0–3; no previous therapy with CCNU, ifosfamide, or cisplatin; no previous high-dose chemotherapy with autologous or allogeneic transplantation; normal baseline bone marrow (BM) function (leukocyte count ≥ 3500/mm3, platelet count ≥ 100,000), normal liver function tests, and normal renal function tests (creatinine level ≤ 1.5 mg/dL, glomerular filtration rate [GFR] > 60 mL/min). Patients with acquired immunodeficiency syndrome-related lymphoma or patients known to have positive human immunodeficiency virus serology were excluded.

Baseline investigations for all patients included a complete history and physical examination, complete blood count, and blood chemistry tests (including the monitoring of lactate dehydrogenase [LDH] levels and urinalysis). Baseline staging procedures included computed tomography (CT) scans of the chest, abdomen, pelvis (and neck if indicated), and a BM biopsy for all patients with NHL with documented BM infiltration in the past or clinical suspicion of BM involvement with current disease recurrence.

Treatment Plan

The CIBO-P dose and schedule included the following: CCNU 60 mg/m2, intravenously (i.v.) on Day 1; ifosfamide 1.5 g/m2, i.v. on Days 1, 2 and 21, 22; bleomycin 5 mg/m2, i.v. on Days 1, 5 and 21, 25; vincristine 1.4 mg/m2, i.v. on Days 1, 8 and 21, 28; and cisplatin 25 mg/m2, i.v. on Days 3, 4, 5 and 23, 24, 25. The cycle was repeated every 42 days. Sodium mercaptoethanesulfonate uroprotection (maximal daily dose, 900 mg/m2) was given i.v. in 3 divided doses. The first dose was given in a mixture with ifosfamide, and the second and third doses were given i.v. in 150 mL of saline over 15 minutes, 4 hours, and 8 hours, respectively, after the beginning of the ifosfamide infusion. Prechemotherapy and postchemotherapy hydration was given on the days of cisplatin administration. The institutional standard antiemetic regimen including metoclopromide, ondansetron, and dexamethasone was given before chemotherapy.

Patients with lymphomatous infiltration after entry into the trial who achieved the disappearance of BM involvement with CIBO-P, were offered central nervous system (CNS) prophylaxis with 12 mg intrathecal methotrexate and 30 mg/m2 ara-C, twice a week for 6 doses.

Dose Modifications

Toxicity was assessed according to WHO toxicity criteria. Cycles were repeated on Day 42 if neutrophil and platelet counts were ≥ 1000/mm3 and ≥ 75,000, respectively. Otherwise, treatment was withheld until hematologic recovery was achieved. On Day 21 of each cycle, chemotherapy administration was delayed for a maximum of 2 weeks if the neutrophil count was < 1000/mm3 and the platelet count was < 75,000. Then, treatment was discontinued until the next cycle. The drug doses were reduced according to given hematologic criteria assessed on Days 1 and 21 of each cycle (Table 1). The doses of all 3 myelotoxic agents were reduced by 25% in subsequent courses if neutropenic fever that required i.v. administration of antibiotics developed. Hematopoietic colony-stimulating factors (CSFs) were not used routinely. However, CSF use was recommended to avoid major reductions in schedule dose intensity. If Grade 3 or 4 nonhematologic toxicity occurred, drug doses were reduced if indicated at the investigator's discretion. In the event of Grade 2 ototoxicity (tinnitus), the cisplatin dose was reduced to 80% with the first occurrence of transient tinnitus and, after the second occurrence, the dose was further reduced to 60%. Cisplatin was omitted in patients with unresolved or recurrent tinnitus. In addition, the cisplatin dose was adjusted if renal impairment, as assessed by GFR, occurred during the study.

Table 1. Hematologic Criteria of Dose Reductions
Neutrophils per μLPlatelets per μCCNU IFOCDDP VCRBLEO
  1. CCNU: lomustine; CDDP: cisplatin; BLEO: bleomycin; IFO: ifosfamide; VCR: vincristine.

≤ 2000≥ 120,000100%100%100%
< 2000 > 1500< 120,000 ≥ 85,00075%100%100%
< 1500 ≥ 1000< 85,000 ≥ 75,00050%75%100%
< 1000< 75,0000%0%0%

Evaluation of Response

Detailed evaluation of tumor response was usually performed using a CT scan every two cycles and at the end of treatment. BM biopsy was repeated at the end of treatment for patients with lymphomatous infiltration on entry into the trial. According to the criteria of Velasquez et al.,2 a decrease of tumor mass by ≥ 50% for a minimum of 4 weeks qualified as a partial response (PR), and the disappearance of all disease evidence for ≥ 1 month qualified as a CR.

Duration of CIBO-P and Consolidation Therapy

Responders received two cycles after the maximal response was documented but not less than three cycles. Patients in Stage I and II also might have received radiotherapy at the end of chemotherapy. High-dose chemotherapy (HDCT) was not an integral part of this trial because the role of consolidation with HDCT was unclear at the time the current study was initiated. CIBO-P was withdrawn if disease progression occurred.

Data Analysis and Statistical Considerations

The statistical analysis specified that a lower limit of the 2-sided 95% confidence interval (95% CI) for the overall response rate that was > 20% would be considered to be evidence of significant activity. After the target sample size of 25 patients was enrolled, safety and efficacy were assessed. The unacceptable response rate of < 20% was ruled out and the trial continued.

The actual total dose of each agent by cycle was calculated by summing the percentage of the protocol dose given in each cycle and dividing it by all the administered cycles. The actual dose intensity (DI) of each agent was calculated by summing the doses (milligrams per square meter) given in all the administered cycles and dividing it by the number of weeks from Day 1 of the first cycle to Day 42 of the last administered cycle.

Survival and other time-based parameters were calculated using the Kaplan–Meier method.18 All efficacy and toxicity end points were updated in October 2004. Time to treatment failure (TTF) was defined as the interval between Day 1 of chemotherapy and the earliest date of disease recurrence, or disease progression, the appearance of another tumor, the withdrawal of study treatment for any reason, the withdrawal of consent, loss to follow-up, or death from any cause. Progression-free survival (PFS) was calculated from the date chemotherapy was started to the date when disease recurrence, disease progression, or death from NHL occurred. For patients who achieved a CR or PR, duration of response was defined as the time from the first assessment that documented the response to the date of disease recurrence or death due to the disease without a previous clinical diagnosis of disease recurrence. Overall survival (OS) was estimated from the date of initiation of chemotherapy to the date of death from any cause. Disease remission duration before CIBO-P was measured from the end of first-line treatment or from the end of salvage therapy for disease recurrences to the date when the most recent disease recurrence was diagnosed.

Factors that were assessed for their influence on the CR rate, TTF, and survival included age, gender, performance status, presence of B symptoms, histology (intermediate grade vs. high grade), presence of bulky disease (≥ 10 cm), serum LDH level, Ann Arbor disease stage (Stage I–II vs. Stage III–IV), number of extranodal sites, number of previous lines of treatment, response to previous therapy, disease remission duration before CIBO-P, average DI, and average total dose of the 5 chemotherapeutic agents of the CIBO-P regimen. The log-rank test19 was used to evaluate binary prognostic factors in univariate analysis. Multivariate analysis was performed on both TTF and survival using the Cox proportional hazards regression model.20 The influence of prognostic factors on the response rate was examined by the Fisher exact test.21 The logistic model22 was used in a multivariate analysis of CR.

SPSS software (version 8.0; SPSS, Chicago, IL) was used in all analyses.

RESULTS

Patients and Treatment

From November 1990 to May 2000, 43 consecutive patients were enrolled in the current study. Two patients were lost to follow-up after receiving one cycle of therapy, and two patients were prematurely removed from the study by their attending oncologist after receiving only one cycle with no documented evidence of disease progression. Thus, 39 patients (90.7%) were evaluated for response. The median follow-up of the study was 108 months (range, 48–144 months). Table 2 shows selected characteristics and pretreatment details of all 43 patients. The median age of the patients was 63 years. All patients had aggressive NHL: 77% had diffuse large B-cell lymphoma, 11% had anaplastic large-cell lymphoma, 10% had peripheral T-cell lymphoma, and 2% had T-cell lymphoblastic lymphoma. Approximately 65% of the patients had Stage III or IV disease, 58% had extranodal disease, 44% had a poor performance status (WHO Grades 2 and 3), 14% had B symptoms, 12% had bulky disease, and 40% had elevated serum LDH levels. Twelve patients (28%) failed to achieve a CR with their induction therapy and were thus considered to have primary refractory disease. Fourteen patients (33%) had primary progressive disease, defined as disease progression during induction treatment or within 90 days after the end of treatment. Fifteen patients (35%) had received ≥ 2 lines of previous chemotherapy. All patients had received previous anthracycline-based chemotherapy. Eight patients (19%) had received previous radiotherapy. Before entry into the study, the median duration of disease remission was 3.9 months. Only 9 patients had a disease remission duration > 12 months.

Table 2. Patient Characteristics and Pretreatment Details
CharacteristicsValue (%)
  • WHO: World Health Organization; LDH: lactate dehydrogenase.

  • a

    Primary progressive disease is defined as disease progression during induction treatment or within 90 days after the end of treatment.

  • b

    Second or subsequent disease recurrence is defined as disease recurrence after achieving complete disease remission.

  • c

    Primary refractory disease is defined as failure to achieve complete disease remission with induction treatment.

  • d

    Patients with primary progressive disease had a disease remission duration of 0 days. Patients with primary refractory disease who received lomustine/ifosfamide/cisplatin/vincristine/bleomycin without a previous clinical diagnosis of disease progression were not evaluated.

Total no. of enrolled patients43 (100)
Male-to-female ratio18/25
Median age (range)63 (24–83 yrs)
Ann Arbor disease Stage III–IV28 (65)
WHO performance status 2 + 319 (44)
Presence of B symptoms6 (14)
Greatest dimension ≥ 10 cm5 (12)
Elevated serum LDH17 (40)
Presence of extranodal disease25 (58)
Histology 
 Diffuse large B-cell lymphoma33 (77)
 Anaplastic large-cell lymphoma5 (11)
 Peripheral T-cell lymphoma4 (10)
 T-lymphoblastic lymphoma1 (2)
Response to previous therapy 
 Primary progressive diseasea14 (33)
 Second or subsequent disease recurrenceb17 (39)
 Primary refractory diseasec12 (28)
Previous lines of treatment 
 Median (range)1 (1–5 lines)
 ≥ 1 line of previous treatment15 (35)
No. of cytotoxic drugs previously received 
 Median (range)6 (3–10)
Previous radiotherapy8 (19)
Disease remission durationd 
 Median (range)117 (0–489 days)
 < 12 mos24 (73)
 ≥ 12 mos9 (27)

The median duration of the treatment was 4 months. Patients received a median of 3 cycles of CIBO-P (range, 1–5 cycles) and the total number of cycles given was 110. CSFs were given to 17 patients (39.5%) over 26 cycles (23.6%). CIBO-P was discontinued in 24 patients (56%) after maximal response was documented. In the remaining 19 patients, CIBO-P was given until treatment failure occurred. CNS prophylaxis was given to three of the six patients to whom such an approach was offered. Two of these three patients responded to CIBO-P with a CR and one with a PR. CNS prophylaxis was not given to the remaining three patients due to patient refusal.

Activity

Based on an intent-to-treat analysis, the overall response rate for the 43 treated patients was 70% (95% CI, 58–82%). Nineteen patients achieved a CR and 11 patients achieved a PR. When only the 39 evaluable patients were analyzed, the overall response rate was 77% (95% CI, 63–90%) (Table 3), with a median duration of response of 6 months. For patients treated for second or subsequent disease recurrences (defined as disease recurrence after achieving a CR), the response rate was 94%. Even in patients with primary progressive and primary refractory disease, > 60% of the patients responded. The median time to a first response was 2 months. The median TTF was 4.9 months for the entire group (Fig. 1), 9 months for patients with a CR, 5.4 months for patients with a PR, and 3.1 months for nonresponders. The median PFS was 6.8 months (Fig. 2). The median PFS among patients with a CR or PR to CIBO-P was 8.5 months. The median duration of the response to CIBO-P was 6 months (95% CI, 4.4–7.7 months), and the median duration of the response among patients with a CR was 7 months. The median OS among all 43 patients was 10.7 months (Fig. 3). At the last follow-up, 37 of the 43 patients had died with lymphoma, 1 was alive with progressive lymphoma, and 5 (11.6%) remained disease free for ≥ 24 months. Three of these patients were alive with no evidence of disease at ≥ 44, ≥ 54, and ≥ 65 months after treatment with CIBO-P. Of the 5 patients with long-term (≥ 24 months) disease-free survival, 3 had achieved a CR with first-line therapy (recurrent lymphoma) and 2 were considered to have primary refractory disease before entry into the study. Only two patients developed CNS involvement during administration of CIBO-P as one of the multiple areas of progression of their disease.

Table 3. Objective Disease Response
CharacteristicsCR/PDPRSDTotal no. of patientsResponse rates (%)95%; confidence interval
  • CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease.

  • a

    Second or subsequent disease recurrence is defined as disease recurrence after a CR.

  • b

    Primary progressive disease is defined as disease progression during induction treatment or within 90 days after the end of treatment.

  • c

    Primary refractory disease is defined as failure to achieve a CR with induction treatment.

Intent-to-treat19/3116437058.3–82.4
Evaluable19/3116397763.8–90.2
Response according to disease sensitivity      
 Second or subsequent disease recurrencesa12/130169482.4–105.6
 Primary progressive diseaseb3/153126740.4–93.6
 Primary refractory diseasec4/133116435.6–92.4
Figure 1.

Time to treatment failure.

Figure 2.

Progression-free survival.

Figure 3.

Overall survival.

Dose Administration

Dose reductions and dose delays in CIBO-P drugs were made for 25 and 30 patients, respectively, and 15 of these patients required both dose reductions and dose delays. For 2 patients, aged 72 and 81 years, respectively, the investigators individually decided to reduce the protocol doses by 30% from the first cycle. Table 4 shows the actual average total dose and DI of each agent received by the treated patients. The lower DIs in comparison to the corresponding total doses were due to some delays in the administration of subsequent cycles because of toxicities.

Table 4. Total Dose and Dose Intensity of Each Agent
Type of dose parameter Percentagea
  • CCNU: lomustine.

  • a

    Percentage of protocol dose in administered cycles.

  • b

    Percentage of protocol dose intensity during administered cycles.

Actual total dose  
 CCNU 87.1
 Ifosfamide 90.4
 Bleomycin 90.2
 Vincristine 87.5
 Cisplatin 94.1
 mg/m2/wkPercentageb
Actual dose intensity  
 CCNU9.175.8
 Ifosfamide797.066.4
 Bleomycin2.972.3
 Vincristine0.762.5
 Cisplatin20.870.1

Prognostic Factors

Factors associated with a significantly higher CR rate by univariate analysis included a CR with previous therapy (12 of 16 patients [75%] with recurrent NHL vs. 4 of 11 patients [36%] with primary refractory NHL vs. 3 of 12 patients [25%] with primary progressive NHL; P = 0.02) and longer duration of disease remission with previous therapy (7 of 8 patients [87%] with disease remission duration ≥ 12 months vs. 9 of 22 patients [41%] with shorter duration of disease remission; P = 0.04). A logistic regression model revealed that a CR with previous therapy was the only independent factor for a CR (P = 0.0058). Parameters that were significantly correlated with a longer TTF (Table 5) included serum LDH, presence of bulky disease, a CR with previous therapy, and average DI of the five drugs of the CIBO-P regimen during the administered cycles. Multivariate analysis demonstrated that a CR with previous therapy and DI were significant independent factors for a longer TTF (P = 0.005 and P = 0.03, respectively). Significant associations between various parameters and OS by univariate analysis are shown in Table 5. By multivariate analysis, 2 factors remained that had significant influence on survival: a CR with previous therapy (P = 0.0014) and serum LDH (P = 0.002).

Table 5. Prognostic Factors for TTF and Overall Survival
Factor (no. of patients)Median TTF (mos)P valueMedian survival (mos)P value
  • TTF: time to treatment failure; LDH: lactate dehydrogenase; NS: not significant.

  • a

    Eight patients were not evaluable for dose intensity.

  • b

    A second or subsequent disease recurrence is defined as disease recurrence after achieving complete disease remission.

  • c

    Primary refractory disease is defined as failure to achieve complete disease remission with induction treatment.

  • d

    Primary progressive disease is defined as disease progression during induction treatment or within 90 days after the end of treatment.

Serum LDH    
 Normal (n = 26)8.40.000713.30.0021
 Elevated (n = 17)4.7 5.4 
Bulky disease    
 Yes (n = 5)5.20.019.84NS
 No (n = 38)8.2 11.4 
Dose intensitya    
 ≤ 60% (n = 14)6.70.0028.40.015
 > 60% (n = 21)10 22.8 
Treatment status    
 Second or subsequent disease recurrenceb (n = 17)8.80.01419.20.005
 Primary refractory diseasec (n = 12)6.8 10.8 
 Primary progressive diseased (n = 14)4.0 7.2 

Toxicity

Table 6 lists the incidence of the main toxicities per patient according to the WHO toxicity criteria. No treatment-related deaths occurred. Myelosuppression was the major toxicity encountered. Grade 3–4 anemia, neutropenia, and thrombocytopenia occurred in 25.5%, 70%, and 51% of patients, respectively. No hemorrhage secondary to thrombocytopenia occurred and only 3 episodes of granulocytopenic fever requiring hospitalization and the i.v. administration of antibiotics developed in 2 patients (5% of patients and 3% of all cycles). Seventeen patients (39.5%) required CSF support during the study. Nineteen patients (44%) required blood product support during CIBO-P treatment with a median of 3 U of red blood cells (range, 2–6 U) and 1 U of transfused platelets. Fourteen patients required only red blood cell transfusions and one patient required only platelet transfusions. Four patients required both red blood cell and platelet transfusions.

Table 6. Toxicity Profile
CharacteristicsMaximum WHO toxicity Grade during study (percentage of patients)
01234
  • WHO: World Health Organization.

  • a All 43 patients were included in the current analysis.

  • b

    Febrile neutropenia occurred in 2 of 43 patients (5%).

Anemia11.59.553.525.50
Leukopenia910203328
Neutropeniab77164228
Thrombocytopenia16.514.018.544.07.0
Nausea/emesis58.021.018.52.50
Stomatitis77.011.511.500
Diarrhea84.04.59.02.50
Renal74.523.02.500
Liver63.014.513.59.00
Neuropathy51.07.014.028.00
Ototoxicity97.502.500

No Grade 4 nonhematologic toxicities were encountered. Grade 3 nonhematologic toxicities were nausea/emesis (2.5%), diarrhea (2.5%), liver toxicity (9%), and peripheral neuropathy (28%). All these events were transient and resolved to Grade 0 or 1. Grade 2 auditory toxicity (tinnitus) occurred in 1 patient. The episode was mild, reversible, and resolved within a few days after cisplatin administration.

DISCUSSION

The results of this prospective Phase II study indicate that the new combination of the five drugs that comprise the CIBO-P regimen is a highly active and well tolerated regimen for patients with recurrent and primary refractory aggressive NHL. Fifty-eight percent of the patients were > 60 years, 61% had primary refractory or primary progressive disease (defined as failure to achieve a CR after induction therapy and disease progression during induction treatment, respectively), 40% had elevated serum LDH levels at the time of initiation of therapy, 44% had a poor performance status, and 35% had received ≥ 2 lines of previous chemotherapy. Despite these poor risk features, CIBO-P achieved an encouraging overall response rate of 77% with 19 (49%) CRs and 11 (28%) PRs. Furthermore, 64% of the patients with primary refractory NHL and 67% of the patients with primary progressive NHL responded to the treatment. The non–cross-resistant nature of CIBO-P was further exemplified by the findinf that patients had previously received a median of six cytotoxic drugs. In the largest series to date of salvage chemotherapy in patients with NHL reported from The University of Texas M. D. Anderson Cancer Center (Houston, TX),2, 3, 21, 23 the response rate ranged from 55% to 69% and the CR rate ranged from 24% to 48%. More recently, Haim et al.24 reported a series of 56 patients treated with a combination of dexamethasone, etoposide, ifosfamide, and cisplatin (DVIP). The objective response rate was 64% and the CR rate was 32%. Because patient selection can significantly influence the results of salvage therapy in patients with lymphoma, it is difficult to compare the current results with those reported by others. Nevertheless, the high response rate (77% with a 49% CR rate) obtained in the current trial cannot be attributed to patient selection bias because this series comprised the majority (90%) of all eligible patients treated at the study center. In the current study, the median duration of response was 6 months, which is similar to the response duration for other salvage programs.21, 23, 24

Several disease and patient characteristics known to be risk factors in the treatment of patients with aggressive NHL were also found to be prognostic factors in the current study. Of these characteristics, a CR with previous therapy was the only independent factor for achieving a second CR and the most important independent factor for TTF and survival by multivariate analysis. The authors found a very high CR rate for patients with recurrent NHL (12 of 16 patients [75%]), indicating that CIBO-P has a curative potential in this group of patients. An association between response to front-line therapy and salvage therapy has also been reported by others investigators.21, 24, 25

However, Velasquez et al.2 failed to show a significant difference in the CR rate with high-dose ara-C and dexamethasone between patients with NHL who had achieved a CR with front-line therapy and those who had not achieved a CR with previous therapy.

Generally, CIBO-P was well tolerated with myelosuppression as the principal toxicity. However, this was easily managed by protocol-specified dose modification with no patients developing thrombocytopenia with hemorrhage and only three episodes of febrile neutropenia. Nonhematologic toxicity was also mild with no Grade 4 toxicity. There were no treatment-related deaths.

Regarding Grade 3 or 4 toxicities, CIBO-P was associated with less severe neutropenia/leukopenia and a lower incidence of peripheral neuropathy compared with other platinum-based regimens such as DHAP and ESHAP.2, 3 Although no cases of permanent renal insufficiency were encountered in our study, Velasquez et al.2 reported this complication in nearly 7% of the patients receiving DHAP. These findings suggest that the CIBO-P regimen tested in the current study might be better tolerated compared with the best established salvage regimens for aggressive NHL.

The treatment of recurrent aggressive lymphomas remains problematic, with the majority of patients showing incomplete or only temporary responses to salvage therapy. For patients < 60 achieving a CR or PR after 2 cycles of conventional chemotherapy, consolidation by HDCT with autologous stem cell transplantation has been shown in the PARMA trial to yield more favorable long-term results than the administration of 4 additional cycles of conventional therapy.26 However, high-dose consolidation has many restrictions, including younger age, absence of BM involvement, and good performance status. A subgroup analysis of the PARMA trial also suggested that patients with an international prognostic index score of 0 at disease recurrence may fare equally well with conventional therapy and with high-dose therapy.27 In the current study, 5 patients (11.6%) achieved long-term (≥ 24 months) disease-free survival and 3 of these patients were alive with no evidence of disease at ≥ 44, ≥ 54, and ≥ 65 months after CIBO-P at last follow-up. Their ongoing complete disease remissions confirm that patients with recurrent NHL may have a chance of cure with conventional salvage therapy. CIBO-P stands out with a particularly high complete disease remission rate. This, however, would render more patients eligible for subsequent high-dose therapy, which might translate into a higher long-term disease remission rate.

The prognosis of patients with primary refractory aggressive lymphomas is dismal.28–32 In the current study, in contrast to other salvage treatments, which have a CR rate of < 15% in primary refractory lymphoma,22, 24, 33 > 60% of patients with primary progressive and primary refractory disease responded to CIBO-P. Furthermore, of the five patients with long-term, disease-free survival, two were considered to have primary refractory disease at the time of initiation of therapy. These findings are of major clinical importance for the design of therapeutic trials for high-risk patients with predicted lower-than-optimum CR and survival rates.34

The finding that CCNU can reach significant levels in the CNS has been another attractive feature of this combination. CNS disease progression in patients responding to CIBO-P occurred in only two patients.

In conclusion, CIBO-P is a novel combination regimen in patients with primary refractory or recurrent aggressive NHL with a poor prognosis. It has clinically significant activity with an acceptable toxicity profile. Thus, CIBO-P has a great potential as a cytoreductive regimen before HDCT. CIBO-P, therefore, warrants further evaluation in patients with first disease recurrence in randomized studies against other platinum-based regimens. Whether addition of the anti-CD20 antibody rituximab, which has been shown to improve the results of the CHOP regimen in the first-line treatment of aggressive B-cell lymphomas,35 will also be of value in patients with recurrent lymphomas is currently being investigated.

Ancillary