Non-Hodgkin's Lymphoma Phase II Study of a High-Dose Ifosfamide

Home , ESHAP, Mitoguazone

Bone Marrow Transplantation (2001) 27, 397–404  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Non-Hodgkin’s lymphoma Phase II study of a high-dose ifosfamide-based chemotherapy regimen with growth factor rescue in recurrent aggressive NHL. High response rates and limited toxicity, but limited impact on long-term survival

K van Besien1, A Rodriguez2, S Tomany3, A Younes2, M Donato1, A Sarris2, S Giralt1, R Mehra1, B Andersson1, J Gajewski1, R Champlin1 and F Cabanillas2

1Division of Medicine, Departments of Stem Cell Transplantation, and 2Lymphoma MD Anderson Cancer Center, Houston, TX; and 3American Medical Association, Chicago, IL, USA

Summary: the 44 patients proceeded to autologous stem cell transplantation and one transplant-related death occurred. The purpose of the study was to evaluate in patients With a median follow-up of 52 months, progression-free with recurrent intermediate-grade NHL, the tolerance survival at 2 years is 38% ± 14% and survival is to and efficacy of an intensive salvage regimen con- 52% ± 15%. Data from these 44 patients were pooled sisting of high doses of ifosfamide, etoposide and mitox- with data on 53 patients who had received salvage treat- antrone with G-CSF support, followed by autologous ment with MINE-ESHAP, for a multivariate analysis of stem cell transplantation and to identify prognostic fac- prognostic factors. In multivariate analysis, serum LDH tors for survival in patients with recurrent aggressive was strongly associated with survival. The use of a more lymphoma. Patients with recurrent intermediate-grade intensive salvage regimen, did not result in a significant NHL under the age of 60 years were eligible. Induction increase in long-term outcome, despite a high response consisted of ifosfamide 10 g/m2 and etoposide 900 mg/m2 rate. In conclusion, duration of treatment, response with G-CSF 5 ␮g/kg twice a day. Upon recovery, rates, treatment-related mortality and survival compare patients underwent stem cell apheresis. Patients achiev- favorably with previous salvage regimens, but recur- ing complete remission (CR) underwent autologous rence remains a major problem. Long-term survival in stem cell transplantation using BEAM conditioning. recurrent large cell lymphoma is influenced more by Those with partial remission (PR) received treatment disease characteristics than by the type of salvage regi- with ifosfamide 10 g/m2, mitoxantrone 20 mg/m2 and G- men used. Bone Marrow Transplantation (2001) 27, CSF 5 ␮g/kg. Those with CR received BEAM, those 397–404. with PR received cyclophosphamide 4.5 g/m2, etoposide Keywords: lymphoma; transplantation; prognostic fac- 1200 mg/m2 and cisplatin 135 mg/m2 with stem cell res- tors cue followed by BEAM. Antibiotic prophylaxis was given with all treatment cycles. The results were compared with those obtained in a prior study that used MINE-ESHAP salvage. Forty-four patients with recur- Commonly used regimens for reinduction of patients with rent intermediate-grade NHL were enrolled between recurrent aggressive non-Hodgkin’s lymphoma (NHL) are March 1994 and September 1996. Median age was 50 either platinum-based (DHAP or ESAP),1 or ifosfamide- years (24–61). Eleven patients had transformed lym- based (most commonly MINE).2 Both types of regimens phoma and seven had a T cell phenotype. Response rate induce responses in approximately two thirds of patients to the high-dose ifosfamide regimen was 77% ± 12% and complete remission rates of approximately 30% to after two cycles and the complete response rate was 40%.3 Autologous transplantation results in durable 41% ± 14%. Myelosuppression was profound but short. remissions in approximately half of the responding Median nadir ANC was 0 and the median duration of patients,3 but lack of response to pre-transplant chemo- ANC Ͻ0.5 × 109/l was 6 days (range 3–12). No severe therapy and recurrence after transplantation limit the clini- infections occurred; 55% of the patients required blood cal impact of this strategy. Overall only approximately 20% transfusion and 42% required platelet transfusions. of patients with recurrent NHL targeted for auto-transplant, Myelosuppression and transfusion requirements were achieve durable remissions.4 similar after the first and second cycles. Thirty-five of Dose-intensity can be optimized by increasing the dose of a particular drug, or by decreasing the treatment interval (ie increasing the dose density).5 We studied a salvage regi- Correspondence: Dr K van Besien, Section of Hematology/Oncology, The University of Illinois at Chicago, 840 South Wood Street (MC787), men consisting of high doses of ifosfamide, etoposide alter- Chicago, Illinois, 60612, USA nating with high-dose ifosfamide and mitoxantrone. With Received 20 September 2000; accepted 24 November 2000 G-CSF support and prophylactic antibiotics, we were able High-dose ifosfamide in NHL K van Besien et al 398 to administer repeated doses of this regimen on a 3- to 4- depended on the response observed. Patients received a week schedule, achieving a dose-intensity that was higher minimum of two treatment cycles and a maximum of four. than previously possible with the MINE regimen. Here we Treatment cycles were repeated at intervals of 4 weeks, present the long-term outcome of patients treated by this when possible. regimen. Furthermore, we compared the outcome of Ifosfamide/etoposide consisted of the following: prior to patients treated on this phase II study with that of patients chemotherapy patients received sodium 2-mercaptoethane- treated between 1990 and 1994 on a phase II protocol with sulphate (mesna) 2 g/m2 i.v. over 2 h. This was followed MINE/ESHAP2 followed by autologous bone marrow by ifosfamide 3.3 g/m2/day mixed with mesna transplantation with BEAC conditioning.6 The combined 2.66 g/m2/day in continuous infusion for 3 consecutive days data from these two studies allow us to identify disease, (total dose of ifosfamide 10 g/m2). After the ifosfamide was patient and treatment-related variables that determine the completed, patients continued to receive mesna 2 g/m2 con- survival for patients with recurrent NHL. tinuous infusion for 12 h. Patients also received etoposide 150 mg/m2 i.v. over 2 h every 12 h for 3 consecutive days (total dose of etoposide 900 mg/m2). Patients started G-CSF Materials and methods 5 ␮g/kg twice a day on the 5th day and continued it throughout the course and until completion of the Patients between the ages of 16 and 61 years with recurrent planned apheresis. aggressive lymphoma or with transformation from more Ifosfamide/mitoxantrone consisted of ifosfamide indolent histology were eligible for this study (DM94–002) 3.3 g/m2 per day for 3 consecutive days with N-acetylcyst- which accrued between 1994 and 1996. Histological docu- eine in a schedule as specified above. This was combined mentation at the time of relapse by biopsy or fine needle with mitoxantrone 20 mg/m2 i.v. on day 1. Patients started aspiration cytology was done whenever feasible. All G-CSF 5 ␮g/kg daily on the 5th day. patients had initially been treated with an anthracycline- CVP consisted of cyclophosphamide 1.5 g/m2/day i.v. containing regimen and had achieved a complete response daily for 3 consecutive days (day −5, −4, −3), etoposide or a stable partial response. They had developed disease 400 mg/m2/day i.v. daily for 3 consecutive days (days −5, progression or recurrence after a treatment-free interval of −4 and −3) and cisplatin 45 mg/m2/day for 3 consecutive at least 3 months. Patients who developed disease pro- days (day −5, −4 and −3). Although this regimen can safely gression during their initial treatment (primary refractory) be given without stem cell rescue, we infused some of the were not eligible. Patients with active CNS disease were stem cells to hasten recovery. Patients were started on G- not eligible and neither were those who were seropositive CSF 5 ␮g/kg on day 1 after the infusion of stem cells and for HIV, HBV and HCV. until recovery of granulocytes. All patients underwent complete restaging including CT BEAM consisted of carmustine 300 mg/m2 i.v. over 1 h scan of the chest, abdomen and pelvis as well as unilateral on day −6, etoposide 100 mg/m2 i.v. over 6 h every 12 h bone marrow aspiration and biopsy. Patients also on day −5, −4, −3, −2 (total eight doses), cytarabine underwent pulmonary function testing and cardiac radio- 100 mg/m2 i.v. over 30 min every 12 h on day −5, −4, −3, nuclide scan or ultrasound. Those with significant abnor- −2 (total eight doses) and melphalan 140 mg/m2 i.v. on day malities (diffusion capacity, functional vital capacity or −1. Patients received an infusion of PBSC on day 0 and ␮ FEV1 less than 50% of predicted or left ventricular ejection started G-CSF 5 g/kg on day 1 after the infusion of fraction less than 45%) were not eligible. Similarly, patients stem cells. with serum creatinine Ͼ1.7 mg%, bilirubin Ͼ2 mg%, gra- Ͻ × 9 Ͻ × 9 nulocytes 1.5 10 /l or platelets 100 10 /l (unless Supportive care due to bone marrow involvement) were not eligible. After every course of chemotherapy, patients received G- ␮ Chemotherapy (Figure 1) CSF 5 g/kg s.c. daily as described above. This dose was doubled to 5 ␮g/kg twice a day after the course of Induction consisted of a cycle of ifosfamide and etoposide ifosfamide/etoposide that was used for stem cell mobiliz- with growth factor support. Stem cell apheresis was perfor- ation. After induction treatment with ifosfamide/etoposide med upon recovery from the first treatment cycle. Patients and ifosfamide/mitoxantrone, patients received oral quino- underwent restaging after every cycle. Those achieving CR lones until recovery of neutrophil counts. After high-dose were consolidated with high-dose BEAM with stem cell CVP or BEAM with stem cell rescue, patients received oral support. Patients achieving partial remission or stable dis- quinolones, fluconazole and acyclovir. Packed red blood ease after ifosfamide/etoposide received a cycle of ifosfam- cells were administered for hemoglobin Ͻ8 g/dl and plate- ide and mitoxantrone. lets for a platelet count Ͻ20 × 109/l. All blood products Patients achieving CR after ifosfamide and mitoxantrone were filtered and irradiated. With BEAM chemotherapy, the were consolidated with high-dose BEAM and stem cell patients received ice chips to prevent mucositis.7 support. Those achieving partial remission or stable disease were consolidated with two courses of high-dose chemo- Post-transplant evaluation and response criteria therapy and stem cell support. The first course consisted of CVP, the second one of BEAM. If progression occurred at Toxicity was assessed according to the criteria of Bearman any time during the treatment, patients were removed from et al.8 Adverse events that could be attributed to infection study. Because of this design, the length of treatment (culture-documented), bleeding, or other medications were

Bone Marrow Transplantation High-dose ifosfamide in NHL K van Besien et al 399 Course 1 Ifosfamide/VP16 Course 2: +G-CSF CR (7) 3 BEAM +stem cell +PBSCT collection +G-CSF n = 44 4*

Course 2: Course 3: Ifosfamide/ 14 BEAM PR (27) mitoxantrone CR SD (10) (15***) +PBSCT +G-CSF +G-CSF (n = 41)**

Course 3: CVP Course 4: PD PR (15) 17 BEAM SD (5) +PBSCT (6) +G-CSF +PBSCT (20) +G-CSF

*: Four patients underwent course 2 while waiting for insurance approval. **: One patient had MI (see text) and was removed from study. PD ***: One patient received TBC as conditioning (see text). (3)

Figure 1 Treatment scheme. not scored as regimen-related toxicity. The maximum tox- Patients were treated with two courses of MINE chemo- icity was the highest grade recorded in any individual organ therapy. After two cycles they underwent restaging. system and the cumulative toxicity score was the sum of Patients with stable or responsive disease underwent bone the highest grades recorded for all eight organ systems. marrow harvest followed by two cycles of chemotherapy Response to therapy was evaluated after every treatment with the ESHAP regimen.2 Those who continued to course, approximately 3 months, 6 months and 1 year after respond then underwent consolidation with high-dose transplant, and annually thereafter. Evaluation consisted of BEAC chemotherapy and autologous bone marrow trans- physical examination, blood counts, chest X-ray, computed plantation.6 tomography of the chest, abdomen, and pelvis and bilateral The conditioning regimen for the transplant consisted of marrow aspirates and biopsies. Gallium scanning, although BEAC. Patients received carmustine 300 mg/m2 i.v. over routinely used, was not considered in the formal assessment 1 h on day −7, etoposide 100 mg/m2 i.v. over 6 h every of response. Additional tests such as immunophenotyping 12 h on day −6, −5, −4, −3 (total eight doses), cytarabine of the blood and bone marrow, lymph node aspiration or 100 mg/m2 i.v. over 30 min every 12 h on day −6, −5, −4, biopsy were performed when clinically indicated. Complete −3 (total eight doses) and cyclophosphamide 35 mg/kg i.v. response (CR) was defined as the disappearance of all clini- over 1 h on day −6, −5, −4, −3 (total four doses). The bone cal and radiological evidence of active tumor. Partial marrow harvest was not purged in the majority of patients, response (PR) was defined as a 50% or greater decrease in but in four cases purging with a monoclonal anti-CD19 the sum of the products of all measured lesions. Stable dis- antibody and immunomagnetic beads was used.9 Patients ease was defined as no change in the size of the measurable routinely received G-CSF 5 ␮g/kg per day subcutaneously lesions, or a response that was less than a partial remission starting the day after marrow infusion and continuing until and no progression for a minimum of 8 weeks. There could an ANC Ͼ500 was achieved. All patients were treated in be no appearance of new lesions for this category. private rooms and received prophylactic antibiotics and antifungal and antiviral prophylaxis. Irradiated blood Ͼ Comparison group: MINE-ESAP-BEAC (DM90–116) products were administered to maintain Hb 8 g/dl and platelets Ͼ20 × 109/l. Between 1990 and 1993, patients with recurrent intermediate-grade lymphoma or with transformation from more Statistical methods indolent histology were eligible for study DM 90–116.6 Eligibility criteria for this study were identical to those of Primary outcomes analyzed were progression-free and DM94–002 except that bone marrow involvement was an overall survival. Probabilities of primary outcomes were exclusion criteria. Staging work-up and response criteria calculated using the Kaplan–Meier product-limit estimate,10 were also similar. and expressed as probabilities with a 95% confidence inter-

Bone Marrow Transplantation High-dose ifosfamide in NHL K van Besien et al 400 val. Data from studies DM90–116 and DM94–002 were (range 32 months to 62 months). Patient characteristics are combined to examine the association of patient-, disease-, summarized in Table 1. Median age at study entry was 50 and treatment-related variables with survival. Univariate (range 24–61). Thirty six patients were treated at the time comparisons used the log-rank test (Table 1).11 Multivariate of first recurrence, eight had had a second recurrence prior analysis used the Cox regression models. All potential risk to treatment on this protocol. Eleven patients had transfor- factors were checked, with time-dependent covariates, to med lymphoma and seven patients had a T cell phenotype. ensure that assumptions of proportionality were met.12 Fac- tors were then tested for their association with death by Response means of forward stepwise selection of variables. All comparisons reaching the 0.05 level of significance are Response rates are summarized in Table 2 (see also presented, but because multiple comparisons were made, Figure 1). The response rate after one course of those with P values greater than 0.01 should be interpreted ifosfamide/etoposide was 77% (95% CI: 64–90) (34/44). with caution. Because of significant interaction of factors, The complete response rate was 16% (95% CI: 5–27) results regarding phenotype and disease stage were com- (7/44). Forty one patients went on to receive a second bined (Table 4). course which consisted of ifosfamide and mitoxantrone. In 37 cases, the second cycle was given to improve response in patients who had achieved PR (n = 27) or stable disease Results (n = 10). In four cases, patients who had achieved CR, received a second cycle for logistical reasons (ie awaiting Patient characteristics DM94–002 insurance approval for transplantation). After completion of both cycles of induction treatment the response rate was Forty four eligible patients were enrolled between March 73% (95% CI: 61–85) (32/44). The complete response rate 1994 and September 1996. All 44 patients were evaluable. was 41% (95% CI: 27–55) (18/44). Thirty five patients Median follow-up for surviving patients is 52 months (77% CI: 65–89) completed consolidation with high-dose chemotherapy. Seventeen patients underwent double con- Table 1 Patient characteristics at study entry and results of univari- solidation with CVP followed by BEAM. Seventeen ate analysis patients received BEAM alone, and one patient received a busulfan-based conditioning regimen (see below). One n 3-year P (log-rank) survival responding patient did not undergo transplantation as planned because he suffered a myocardial infarction prior n 97 44% ± 10% to admission for high-dose chemotherapy. This event was Gender likely unrelated to his treatment. Female 35 37 0.38 Male 62 49 Disease transformation Treatment-related toxicity Transformed 29 31 0.17 Not transformed 68 50 Myelosuppression: Ifosfamide-etoposide and ifosfamide- Phenotype mitoxantrone with G-CSF support resulted in profound B cell 79 48 0.05 neutropenia. The median nadir granulocyte count was 0 Non-B cell 18 26 after ifosfamide/etoposide (range 0–0.2) and after Age adjusted IPIb 0 27 71 0.00003a ifosfamide/mitoxantrone (range 0–0.8). The median dur- 14244ation of neutropenia (ANC Ͻ0.5 × 109/l) was 6 days after 22716ifosfamide/etoposide (range 4–10) and 5 days after Involvement of р1 extranodal sitec 79 47 0.26 ifosfamide/mitoxantrone (range 3–12). Information on Involvement of Ͼ1 extranodal site 15 33 LDH normalc 55 61 0.00002 transfusion requirements was available for 42 of 44 patients LDH elevated 42 21 receiving ifosfamide/etoposide. Twenty four of these Performance status 0–1 93 44 0.83 required platelet transfusions (median 1, range 0–2). Performance status Ͼ1450 Eighteen required blood transfusion (median 0, range 0–8). Stage I–II 46 58 0.008 Similarly, information on transfusion requirements Stage III–IV 51 33 Time to first recurrence Ͼ1 yearc 44 55 0.37 was available for 38 of 41 patients receiving Time to first recurrence Ͻ1 year 39 50 ifosfamide/mitoxantrone. Twenty five of 38 required a Beta 2 microglobulin р2.0c 45 52 0.07 Beta 2 microglobulin Ͼ2.0 44 37 First relapse 78 44 0.96 = ϾOne relapse 19 44 Table 2 Response and outcomes DM94-002 (n 44) Protocol DM90–116 52 44 0.63 Response rate after one cycle (ifosfamide-etoposide) CR: 7 (16%) DM94-002 44 44 CR + PR: 34 (71%) Response rate after two cycles (ifosfamide-etoposide CR: 18 (41%) + aP value for comparison between the three groups. P value for age- and ifosfamide-mitoxantrone) CR PR: 32 (73%) adjusted IPI 0 vs age adjusted IPI 1 = 0.018. P value for age-adjusted IPI Patients consolidated with transplantation 35 (77%) ± 1 vs age-adjusted IPI 2 = 0.005. 2 year progression-free survival 38% 13% ± bInformation missing in one case. 2 year survival 52% 15% cInformation missing in Ͼthree cases.

Bone Marrow Transplantation High-dose ifosfamide in NHL K van Besien et al 401 median of one platelet transfusion (range 0–4). Twenty 1.0 seven required blood transfusions (median 2, range 0–6). LDH normal (n = 54) 0.9 LDH elevated (n = 42) Non-hematologic toxicities were mild. Grade II toxicity 0.8 occurred in only one patient, who had a severe pain reaction 0.7 to etoposide with each treatment cycle. Other toxicities 0.6 included mild mucositis and alopecia. Ifosfamide-related 0.5 encephalopathy occurred in one patient. Fatal or life-threat- 0.4 ening toxicities did not occur. 0.3 Toxicity of high-dose chemotherapy with stem cell trans- 0.2 plantation was also limited to myelosuppression. The 0.1 Ͼ median time to recovery of ANC 0.5 was 9 days after 0 CVP (range 7–12) and after BEAM (range 7–12). After Cumulative proportion surviving 0 1 2 3 4 5 6 7 8 9 10 CVP, the maximum observed toxicity was grade I. After Survival time in years BEAM, one case of grade II pulmonary toxicity occurred that was reversed with steroid treatment. The patient with Figure 3 Survival according to serum LDH. The difference in expected a history of allergic reaction to etoposide was felt not to survival between the two groups are highly significant (P = 0.00002). be likely to tolerate BEAM. Instead he received a thiotepa, Forty-two of the 97 patients can be assigned to the adverse prognostic group. busulfan and cyclophosphamide combination that has pre- 13 viously been used for the treatment of NHL. He detailed in Table 1. Follow-up for surviving patients is 5.4 developed ARDS and died on day 17 after transplantation. years (range 3.3–9.2 years). Thirty seven patients remain alive and twenty seven are free of disease. Survival at three Survival and disease-free survival and recurrence rate years is 44% ± 10%, progression-free survival at 3 years is 33% ± 10% (Figure 2). A multivariate analysis showed that Twenty of the 44 patients remain alive and 14 are pro- an increased serum LDH (analyzed as a categorical vari- gression free. Progression-free survival at 2 years is 38% able: elevated vs normal) was significantly associated with (95% CI: 24–52). Survival at 2 years is 52% (95% CI: 37– worse survival (Figure 3). Disease stage was an inde- 67). All but two treatment failures were due to disease pro- pendent predictor for survival in patients with non-B cell gression (one treatment-related death after transplant and lymphoma. Phenotype (B cell vs non-B cell) was an inde- one death from adenocarcinoma of unknown primary). Dis- pendent predictor for survival in patients with advanced ease progression occurred during induction treatment with disease stage. On the other hand, among patients with B ifosfamide in six patients. Three additional patients cell NHL, no significant survival advantage was associated developed disease progression after CVP. In the remainder with lower disease stage. Similarly, B cell phenotype was it occurred after autologous transplantation, usually within not associated with an improved outcome among patients the first 6 months after completion of treatment. There were with low disease stage. Other disease- or patient-related three recurrences more than 3 years after enrollment. Late variables, such as duration of first remission, age or progression presented as low-grade histology in one patient extranodal disease, did not correlate with survival. and with aggressive histology in two. Importantly, the salvage regimen used did not correlate with survival (Figure 4). Prognostic factors (Table 4)

For the analysis of prognostic features relating to survival, Discussion the data on the 44 patients participating in DM94–002 were combined with those on 53 patients participating in DM90– Many groups have tested intensive ifosfamide-based sal- 116 (Mine-Eshap-BEAC), the characteristics of whom are vage regimens for reinduction therapy of recurrent NHL.

1.0 1.0 Survival DM90-116 (n = 52) 0.9 DFS 0.9 DM94 002 (n = 45) 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1

Cumulative proportion surviving 0.0

Cumulative proportion surviving 0.0 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Survival time in years Survival time in years

Figure 2 Survival and progression-free survival for 97 patients partici- Figure 4 Survival according to treatment assignment. DM90–116: pating in two consecutive studies. MINE-ESHAP-BEAC vs DM94–002: high-dose ifosfamide protocol.

Bone Marrow Transplantation High-dose ifosfamide in NHL K van Besien et al 402 Various doses and combinations of ifosfamide with other The response rate of 77% with this regimen was achieved agents have been reported (Table 3). We chose to evaluate within one or two cycles of treatment. In addition to the a regimen of high-dose ifosfamide with etoposide, and high response rates, this regimen was used for stem cell alternated it with ifosfamide and mitoxantrone. The choice collection. As detailed in another publication, a median of these agents was based on their demonstrated activity in number of 13.1 × 106 CD34 positive (range 4.1–148) cells large cell NHL, the fact that they are not commonly used per kg were collected in a median of two phereses (range in front-line treatment and encouraging results from a pre- 1–10) during the recovery from the first cycle of chemo- vious pilot study.14 The agents are similar to those used therapy.21 This high mobilization efficiency may in part be in the MINE regimen,2 but represent a considerable dose due to the combination of an alkylating agent with etopo- escalation (Table 3). We considered the achievement of side as previously shown by Demirer et al22 and is again complete remission an important intermediary end-point. similar to the data with ICE or other ifosfamide combi- We hypothesized that increased dose-intensity might nations (Table 3).19,23,24 increase the rate of partial and complete remissions, and Responding patients were consolidated with BEAM and ultimately result in improvement in long-term outcome autologous stem cell transplantation or with double consoli- after autologous transplantation.15–19 dation with CVP and BEAM if they had achieved a partial With filgrastim and prophylactic antibiotics, we were remission, further increasing the intensity of this regimen. able to administer this regimen at 4-week intervals. Myelo- The entire treatment sequence consisting of salvage chemo- suppression was profound, but relatively short. With anti- therapy and autologous transplantation lasted a median of biotic prophylaxis and transfusion support, no life-threaten- 111 days (range 68 to 167 days), which is considerably ing complications occurred. The nadir granulocyte count shorter than salvage regimens that are traditionally used. was much lower than that observed with the ESHAP or the The median duration of treatment with the MINE-ESHAP- MINE regimen, but no deaths due to neutropenic infection BEAC sequence, used in our previous study,5 was 180 days occurred with this regimen in contrast to five deaths out of (range 141–255, P Ͻ 0.01). With a median follow-up of 4. 122 patients after ESHAP,1 and two deaths out of 61 years, approximately 40% of all the patients continue to be patients under the age of 60 treated with MINE-ESHAP.2,20 progression-free. The limited duration of neutropenia and the use of prophy- Unfortunately, only a minority of patients achieved dur- lactic quinolones are probably responsible for the low able remissions, despite consolidation with autologous incidence of severe infections. transplantation, and multivariate analysis indicated that

Table 3 Recently reported ifosfamide-based salvage regimens for NHL and Hodgkin’s disease (without stem cell support)

Author Ifosfamideb Etoposide Other G-CSF Used for stem % toxic % response cell death CR/PR mobilization

Rodriguez et al2 MINE(2) 4 g/m2 195 mg/m2 mitoxantrone 8 mg/m2 none No 21/27 Stamatoullas et al32,33 IVAM 7.5 g/m2 450 mg/m2 cytarabine 300 mg/m2 5 ␮g/k Yes 0% 61/26 methotrexate 3 g/m2c Baars et al34 IE 3–4 g/m2 300 mg/m2 5–10 ␮g/kg Yes 0% not reported Garay et al35 MIZE 4.5 g/m2 300 mg/m2 idarubicin 12 mg/m2 not routinely No 9% 46/26 McQuaker et al36 G-IVE 9 g/m2 600 mg/m2 epirubicin 50 mg/m2 300 ␮g Yes NR NR Aurlien et al23 MIME 5 g/m2 300 mg/m2 methotrexate 30 mg/m2 5 ␮g/kg Yes NR NR mitoguazone 500 mg/m2 Ribrag et al37 VIP 6 g/m2 375 mg/m2 cisplatin 100 mg/m2 none No 0% 38/29 Bonfante et al38 12 g/m2 vinorelbine 50 mg/m2 5 ␮g/kg No 0% 38/38 Haim et al39,40 DAIP 4.8 g/m2 cytarabine 300 mg/m2 none No 3% 37/20 cisplatin 80 mg/m2 dexamethasone 160 mg Mayer et al41 MINE 4 g/m2 195 mg/m2 mitoxantrone 8 mg/m2 10–16 ␮g/kg Yes 0% 18/45 Mayer et al41 VIM 6 g/m2 270 mg/m2 methotrexate 30 mg/m2 10–16 ␮g/kg Yes 0% 17/33 Moskowitz et al19 ICE 5 g/m2 300 mg/m2 carboplatin 5 (AUC) 5 ␮g/kg Yes 0% 66% CR+PR McBride et al42 EPIC 5 g/m2 400 mg/m2 prednisolone 500 mg none No 0% 37/22 carboplatin 240 mg/m2 Lopez et al43 IAPVP-16 5 g/m2 300 mg/m2 cytarabine 4.8 g/m2 5 ␮g/kg No 0% 39/41 methylprednisolone 400 mg/m2 Anselmo et al44 IVE 7.5 g/m2 450 mg/m2 epirubicine 100 mg/m2 some patients Yes 6% CR 50% Salar et al45 IFOVM 10 g/m2 900 mg/m2 methylprednisolone 300 mg/m2 5 ␮g/kg Yes 0% 55% CR+PR Current report Ifosfamide/ 10 g/m2 900 mg/m2 5 ␮g/kg Yes 0% 79% CR+PR etoposidea Current report Ifosfamide/ 10 g/m2 mitoxantrone 20 mg/m2 5 ␮g/kg No 0% mitoxantronea

All doses are total doses (as opposed to daily dose). aCurrent protocol. bIfosfamide is always administered with mesna rescue. cWith leucovorin rescue.

Bone Marrow Transplantation High-dose ifosfamide in NHL K van Besien et al 403 there was no major survival benefit to the use of the more candidates for high-dose chemotherapy. Disease stage and intensive high-dose ifosfamide-based regimens compared disease phenotype provide additional prognostic infor- with MINE/ESHAP (Figure 3). While the limited number mation and could be used to further define the prognosis of patients would allow only detection of major differences, in patients with normal LDH. Only patients with favorable overall survival was clearly affected more by the patient’s prognostic features such as low LDH and B cell phenotype disease status than by the type of salvage chemotherapy should be entered on studies of salvage chemotherapy and used. These data are reminiscent of the recent data of Mos- autologous transplantation. Other patients should be offered kowitz et al19 where, despite an impressive response rate, participation in investigational treatments that may be more durable survival was achieved in only 33% of patients. phenotype-specific or that exploit immune effects. Unfortunately, in the setting of recurrent NHL, the impact of high-dose ifosfamide regimens on long-term outcome is limited when compared with more commonly used salvage References regimens. Duration of response in recurrent NHL may be more dependent on patient characteristics than on the type 1 Velasquez WS, McLaughlin P, Tucker S et al. ESHAP–an of salvage administered.1,2,4,25,26 effective chemotherapy regimen in refractory and relapsing Hence, it becomes important to be able to distinguish lymphoma: a 4 year follow-up study. J Clin Oncol 1994; 12: 1169–1176. patients that will benefit from salvage therapy and autolog- 2 Rodriguez MA, Cabanillas FC, Velasquez W et al. Results of ous transplantation from those who will not obtain durable a salvage treatment program for relapsing lymphoma: MINE responses. Several groups have recently reported on prog- consolidated with ESHAP. J Clin Oncol 1995; 13: 1734–1741. nostic features in patients with recurrent aggressive 3 Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone NHL.4,26–28 We confirmed that serum LDH provided strong marrow transplantation as compared with salvage chemo- independent prognostic information in patients with recur- therapy in relapses of chemotherapy-sensitive non-Hodgkin’s rent NHL. The association of disease stage with survival lymphoma. New Engl J Med 1995; 333: 1540–1545. was less significant (P = 0.02) and there was a strong inter- 4 Blay J-Y, Gomez F, Sebban C et al. The international prog- action of this parameter with phenotype (Table 4). Patients nostic index correlates to survival in patients with aggressive with B cell phenotype had a better outcome than others, lymphomas in relapse: analysis of the PARMA trial. Blood 1998; 92: 3562–3568. especially when patients with advanced disease were com- 5 Rodriguez MA, van Besien K, Swan F et al. MINE-ESHAP- pared. As in other studies, B cell lymphoma constituted BEAC: an induction consolidation program for relapsed inter- the majority of the patients, and the sample of non-B cell mediate grade lymphoma. ASCO Proc 1995; 14: 397. lymphomas was quite small and heterogeneous.29,30 There- 6 Van Besien KW, Tabocoff J, Rodriguez MA et al. Intensive fore, these data should be interpreted with caution. They chemotherapy with the BEAC regimen and autologous bone are however consistent with recent reports that indicate a marrow transplantation in patients with refractory or recurrent superior outcome for patients with B cell NHL.29,30 intermediate grade and immunoblastic lymphoma; toxicity, In conclusion, high-dose ifosfamide-based regimens with long-term follow-up and identification of prognostic factors. growth factor support induce high response rates, with lim- Bone Marrow Transplant 1995; 15: 549–555. ited toxicity, a shorter duration of treatment and with the 7 Meloni G, Capria S, Proia A et al. Ice pops to prevent melphalan induced stomatitis. Lancet 1996; 347: 1691–1692. ability to mobilize large numbers of stem cells, but they do 8 Bearman SI, Appelbaum FR, Buckner CD et al. Regimen- not have a major impact on duration of remission in related toxicity in patients undergoing bone marrow transplan- 26 patients with recurrent aggressive NHL. Serum LDH pro- tation. J Clin Oncol 1988; 6: 1562–1568. vides a reproducible parameter that allows the assessment 9 Van Besien K, Rodriguez M, Amin K et al. Intensive reinduc- of prognosis in patients with recurrent lymphoma who are tion with high-dose ifosfamide/VP16 and ifosfamide/ novantrone followed by BEAM and stem cell transplant for patients with recurrent lymphoma. ASCO Proc 1997; 16: 21a. Table 4 Adverse prognostic features for survival by multivariate 10 Shimamoto Y, Pichyangkul S, Khan A. Enhancement of cell- analysis (data from DM90116 and DM94–002, n = 97) mediated cytotoxicity by recombinant tumor necrosis factor (TNF␣). Proc Soc Exp Biol Med 1988; 189: 310–316. Relative risk P value 11 Altman DG. Analysis of survival times. Practical Statistics for Medical Research. Chapman and Hall, London, 1991, LDH (elevated vs normal)a 6.03 (2.82–12.89) 0.0001 365–395. Stage 3/4 vs stage 1/2b 1.9 (1.1–3.2) 0.02 12 Cox DR. Regression models and life tables (with discussions). Stage 3/4 non-B cell vs stage 1/2 9.09 (2.5–33) 0.0008 J Roy Stat Soc (Series B) 1972; 34: 187–220. non B cellb 13 Przepiorka D, Nath R, Ippoliti C et al. A phase I–II study Stage 3/4 non-B cell vs stage 3/4 6.25 (2.3–16.7) 0.0004 of high-dose thiotepa, busulfan and cyclophosphamide as a b B cell preparative regimen for autologous transplantation for malignant lymphoma. Leuk Lymphoma 1995; 17: 427–433. aLDH was time dependent covariate; it ceased to have an impact on sur- 14 Rodriguez MA, Swan F, Hagemeister F et al. Sequential vival beyond 1 year. b intense dose chemotherapy and peripheral stem cell support There was an interaction between phenotype and stage. No significant in refractory lymphoma. ASCO Proc 1994; 13: 1320. difference in survival was found between stage 3/4 B cell and stage 1/2 B cell. 15 Meyer RM, Hryniuk WM, Goodyear MDE. The role of dose No significant difference in survival was found between stage 1/2 non-B intensity in determining outcome in intermediate-grade non- cell and stage 1/2 B cell. Hodgkin’s lymphoma. J Clin Oncol 1991; 9: 339–347. Phenotype did not have independent prognostic value, outside the sub- 16 Johansen MJ, Madden T, Mehra RC et al. Phase I pharmaco- group of patients with stage 3/4 disease. kinetic study of multicycle high-dose carboplatin followed by

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