There is great interest in chemotherapies for relapsed or refractory lymphomas that are both directly effective against the lymphoma and able to mobilize PBSCs for rescue after high-dose chemotherapy (HDC). Twenty-eight patients with relapsed or refractory lymphomas were treated with a shortened, intensified MJMA regimen (mitoxantrone 10 mg/m2 i.v. day 1, carboplatin 200 mg/m2 i.v. days 1–2, methylprednisolone 500 mg/m2 i.v. days 1–3, cytarabine 2000 mg/m2 i.v. day 3) for six cycles every 21 days. A median of five cycles/patient was administered. Nineteen patients had complete responses, seven partial responses and two no responses. The only remarkable toxicity was hematological. In 18 patients who were candidates for HDC, a mean of 10.45 × 106 CD34/kg of patients' body weight was collected (range: 3.70–24.88 × 106/kg). Eleven patients underwent transplantation, which converted two of four partial responses into complete responses. The median follow-up was 49 months. Survival parameters were not related to relapsed/refractory status or to the time from the last chemotherapy, but were related only weakly to the number of prior chemotherapies. Outpatient MJMA is a feasible and very effective salvage chemotherapy per se. The complete response rate is high and it is a powerful PBSC mobilizer.
The management of patients with relapsed or refractory lymphomas, both Hodgkin and non-Hodgkin forms, is still a very challenging clinical problem.
Relapses after complete responses achieved with modern front-line treatments occur in about 20% of patients with Hodgkin's lymphoma1, 2, 3 and in 50% of those with non-Hodgkin's lymphoma,4, 5 whereas less than 6% and about 10%, respectively, develop progressive disease early after first-line chemotherapy (the truly refractory subjects). Nearly 50% of all these patients can be rescued by means of high-dose chemotherapy (HDC) followed by autologous or allogeneic BMT.6 However, the response to transplantation depends on a number of factors such as presentation of the disease, type and number of previous therapies, the patient's prognostic factors, response to debulking chemotherapy administered before HDC and the type of pre-transplant conditioning regimen. In particular, the chemosensitivity shown before BMT is a crucial discriminator of the final outcome, the complete disappearance of all signs and symptoms being the ideal condition. Many chemotherapy protocols have been designed for pre-transplant cytoreduction and achieve CRs in 20–50% of cases.
Here, we report the results of a cytoreductive regimen that includes non-cross-resistant drugs—mitoxantrone, carboplatin and cytarabine—that are highly effective both against lymphoma and in mobilizing PBSCs, allowing adequate harvest of CD34+ cells for autologous BMT (ABMT).
Materials and methods
A histologically confirmed diagnosis of Hodgkin's or non-Hodgkin's lymphoma was necessary for patients to enter this study. The patients were also required to have failed to benefit from at least one full course of multiple drug chemotherapy, to be aged 20–75 years, to have a normal blood count and normal cardiac, hepatic and renal function, and to have measurable disease. In particular, patients who did not achieve a CR with the up-front chemotherapy were considered refractory, whereas those who experienced signs and/or symptoms of disease after a proven CR were considered relapsed. Subjects who did not respond to radiotherapy as their only treatment were excluded. Patients gave their written informed consent to undergo MJMA chemotherapy.
A total of 28 patients, 4 with Hodgkin's and 24 with non-Hodgkin's lymphoma, were recruited into this study between January 2000 and December 2006. Their clinical characteristics are detailed in Table 1. All stage IV patients with non-Hodgkin's lymphoma and one with Hodgkin's lymphoma had BM involvement before the start of the MJMA regimen. Table 2 reports the previously administered therapies and the prognostic evaluation made before the start of MJMA according to the International Prognostic Index described by Shipp et al.7 for patients with non-Hodgkin's lymphoma and the International Prognostic Score reported by Hasenclever et al.8 for those with Hodgkin's lymphoma.
The shortened and intensified MJMA chemotherapy regimen was a 3-day variant, with a 3-week interval, of the original 5-day MiCMA regimen with a 4-week interval.9, 10 The modifications were made to increase both the size of the dose of carboplatin and the dose intensity of all the drugs, while maintaining the feasibility of the treatment on an outpatient basis and without changing the cumulative doses administered. The modified schedule consisted of mitoxantrone 10 mg/m2 i.v. on day 1, carboplatin 200 mg/m2 daily i.v. on days 1 and 2, cytarabine 2000 mg/m2 i.v. on day 3 and methylprednisolone 500 mg/m2 daily i.v. on days 1–3. Treatment was repeated at 21-day intervals for a total of four to six cycles. The theoretical mean dose intensity of all the drugs was increased by 25% and the size of the dose of carboplatin was doubled.
The general evaluation of the patients included computed tomography, abdominal and cardiac ultrasonography, and BM biopsy before the MJMA therapy. After the end of chemotherapy, all clinical manifestations of lymphoma were reassessed with the same methods used before the start of therapy. Positron emission tomography was employed in the staging or restaging of the 12 most recently recruited patients.
All patients who started therapy were considered evaluable for response. The response grades were evaluated using the revised criteria of Cheson et al.11 OS was calculated from the start of therapy to death from any cause. PFS was measured for all patients from the start of therapy to the date of treatment failure, disease progression, relapse or death related to the disease or to the treatment. Relapse-free survival was calculated for complete responders from the end of treatment to the date of relapse or death from the disease.12 Survival curves were calculated using the method of Kaplan and Meier.13
Toxicity was evaluated according to the standard ECOG criteria.14
All patients were evaluable for response and toxicity. Their follow-ups ranged from 5 to 82 months (median: 49 months). Overall, 145 cycles of MJMA were given, with a median of five cycles per patient: two patients received only three cycles because of their lack of response, seven patients received four cycles, five patients received five cycles, 13 patients received six cycles and one patient received eight cycles.
On average, the MJMA regimen was delivered at 84% of the planned dosage and with a 17% delay with respect to the scheduled time frame.
At the end of chemotherapy, 19 patients (68%) had achieved CR and seven had obtained PR (25%) for an overall response rate of 93%. Two patients (7%) did not respond to the MJMA chemotherapeutic regimen. Table 3 reports the grade of individual response to MJMA chemotherapy related to the disease status at the start of the treatment (relapsed or refractory), to the time interval elapsed from the end of the last chemotherapy, to the number of chemotherapy regimens received earlier, to the preceding marrow transplantation procedures and to the administration of radiotherapy. There was no clear relationship between response and any of these parameters.
No patients died of MJMA-related toxicity. The patients did, however, experience severe hematological toxicity (grades 3 and 4 of the WHO scale): severe neutropenia was observed in all patients and severe thrombocytopenia in 18 out of 28. G-CSFs were administered on demand at the first record of a neutrophil count <1.00 × 109/l, and were then used prophylactically at the same individual efficient doses in every following cycle. Anemia, with a hemoglobin concentration below 80 g/l (WHO grade 2), was observed in five patients. The relatively low prevalence of severe anemia was probably due to the prophylactic administration of EPO (or, more recently, of darbepoetin) when the concentration of hemoglobin was found to be below 100 g/l. Non-hematological toxicity was negligible.
Eighteen patients aged 27–64 years, for whom consolidation therapy with HDC and subsequent PBSC rescue was judged appropriate and feasible, underwent marrow stimulation with G-CSF after one of the first three cycles (300 μg every 12 h, from day 5 until completion of the leukapheresis procedures). PBSC mobilization was successful in all of these patients, with a mean yield of CD34-positive cells of 10.45 × 106/kg of patient's body weight (range: 3.70–24.88). A single leukapheresis was sufficient in 15/18 subjects, whereas two leukaphereses were necessary in the remaining three. The median time between the first day of the cycle and PBSC harvest was 13 days (range: 11–17). Six patients chose not to undergo ABMT because of their rapid and complete response to MJMA treatment, and one who responded partially refused any further treatment. Therefore, 11 patients were transplanted after MJMA: seven of these had no evidence of disease, whereas four underwent transplantation having obtained a partial response to MJMA chemotherapy. Two of these four patients achieved CR after ABMT (one in spite of a severe CMV infection), whereas the pre-transplant status did not improve substantially in the other two. Neither response to MJMA nor PBSC mobilization was influenced by the inclusion of rituximab in earlier treatments.
Ten deaths have been recorded, eight because of relapse or progression of the lymphoma and two because of infections (septic shock in a 68-year-old men 5 months after the last cycle of MJMA and a CMV infection in a 60-year-old women 10 months after ABMT).
The survival curves illustrated in Figures 1, 2 and 3 show that the response in terms of OS, disease-free survival and PFS to MJMA—and to PBSCT, when administered—was not influenced by the presence of a relapsed or refractory disease (differences are not statistically significant). Only the number of previously administered chemotherapy regimens (one vs two or more) had a slight effect in separating the curves of PFS (Figure 4), although this was not statistically significant (P=0.110).
The best conventional salvage treatment for patients with relapsed or refractory lymphomas, effective for both cytoreduction and PBSC mobilization, is not known. Randomized trials are difficult to organize in this setting of patients because of the number of clinical variables that play important clinical roles and would require as many stratifications (histology, tumor bulk, response to and number of previous treatments, symptoms, presence of prognostic factors before salvage therapy). Moreover, in all series, most of the patients treated go on to receive HDC with ABMT, and this makes it difficult to compare the long-term intrinsic efficacy of conventional salvage chemotherapy. However, as not all refractory or relapsed patients can actually address HDC (because of comorbidity, frailty, advanced age and risk of infections), every effort must be made to maintain these patients in an acceptable clinical condition and to prolong their life with conventional chemotherapy. The ideal salvage therapy for both Hodgkin's lymphoma and non-Hodgkin's lymphoma should be an efficient mobilizer of PBSC, have low hematological and non-hematological toxicity and, in the meantime, have sufficiently high cytoreductive activity as to be administered for an adequate number of cycles with good results in those patients who cannot undergo ABMT.
The first experiences with a 5-day MicMA protocol (or MJMA, which is the same as, in this acronym, ‘J’ refers to one of the first abbreviations of carboplatin, JM-8) in relapsed or refractory lymphomas were those of Sica et al.9 (18 patients) and La Sala et al.15 (31 patients) who obtained CRs in 22 and 45% of patients, respectively, and partial responses in 44 and 13% (response rates: 66 and 58%, respectively). Sica et al.9 showed the regimen's ability to mobilize PBSC. La Sala et al.15 recorded—as in the present series—no differences in the response rate of relapsed and refractory patients.
Subsequently, Ortu La Barbera et al.10 administered the same MiCMA regimen to 29 patients with relapsed or refractory Hodgkin's lymphoma, 34% of whom responded completely and 52% partially to this chemotherapy regimen before undergoing HDC with PBSC rescue. More recently, Sorà et al.16 used the same treatment protocol in 85 patients with relapsed or refractory non-Hodgkin's lymphoma and achieved CRs in 26% and partial responses in 44%; 77% of the patients were subsequently transplanted.
In this study, the overall response rate to the shortened and intensified MJMA chemotherapy regimen was high and, moreover, included a decidedly higher proportion of complete responses than had those recorded in the preceding experiences with the same drug combinations, except from that by La Sala et al.15 One possible explanation for this is that Sica et al.,9 Ortu La Barbera et al.10 and Sorà et al.16 administered only two or three cycles of the MJMA regimen and admitted patients to HDC and ABMT soon after PBSC harvesting. La Sala et al.15 administered five or six cycles, as we did in the present series, going on with a further two to four cycles after that used for PBSC mobilization and harvesting. This might have allowed greater exploitation of the intrinsic antilymphoma action of the regimen. As the number of cycles administered was the same in our series and in that of La Sala et al.,15 the explanation of the higher response rates in our series may be the double the dose size of carboplatin and the dose intensification of all the drugs administered to our patients.
The results obtained in this series are good not only in comparison with other experiences with MiCMA (or MJMA), but also in comparison with a number of other recently tested pre-transplant salvage regimens: those investigated or tested again in the last 3 years are reported in Table 4. The populations of patients in these studies are heterogeneous (also with respect to the proportion of refractory cases) and numerically limited; any comparisons are therefore fraught with risks. However, on the whole, the review shows that percentages of patients who achieved a complete response (the most reliable condition to have stable results from subsequent HDC) ranged from 3 to 50%, frequently with a discrete reduction in the refractory subset, and generally with a trend toward the administration of only two or three cycles (never more than four). On this background, the outcome after the short, intensified MJMA chemotherapy regimen seems of interest, especially in consideration of the proportion of refractory cases (40%), the responses obtained by these patients (not different from those of relapsed subjects) and the rather advanced age range of the patients. Moreover, toxicity was limited to the hematological compartment. The regimen was safely administered on an outpatient basis, with a strong capacity to mobilize PBSC, and showed that six courses can generally be administered within 4 months. It seems to be equally active in patients with Hodgkin's or non-Hodgkin's lymphoma (more on the basis of previous analogous experiences than from our study, considering the low number of patients with Hodkgin's lymphoma included in our series), and its efficacy appears to be reduced only by the number of chemotherapy regimens administered earlier. It is possible that the effort to complete six courses whenever possible, without stopping the therapy after the mobilizing cycle, was an additional factor in the performance of the regimen. These results need to be confirmed by other studies. Further improvements might be derived from the combination of the drugs of MJMA with gemcitabine and/or rituximab in CD20-positive lymphomas.
Macdonald DA, Connors JM . New strategies for the treatment of early stages of Hodgkin's lymphoma. Hematol Oncol Clin North Am 2007; 21: 871–880.
Diehl V, Engert A, Re D . New strategies for the treatment of advanced Hodgkin's disease. Hematol Oncol Clin North Am 2007; 21: 897–914.
Canellos GP . Relapsed and refractory Hodgkin's lymphoma: new avenues? Hematol Oncol Clin North Am 2007; 21: 929–941.
Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993; 328: 1002–1006.
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B-cell lymphoma. N Engl J Med 2002; 346: 235–242.
Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemosensitive non-Hodgkin's lymphoma. N Engl J Med 1995; 333: 1540–1545.
Shipp MA, Harrington D, Anderson JR, Armitage JO, Bonadonna G, Brittinger JG et al. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329: 987–994.
Hasenclever D, Diehl V . A prognostic score for advanced Hodgkin's disease. N Engl J Med 1998; 339: 1506–1514.
Sica S, Di Mario A, Salutari P, Etuk B, Jovino MS, Pierelli L et al. Sequential peripheral blood progenitor cell transplantation after mobilization with salvage chemotherapy and G-CSF in patients with resistant lymphoma. Am J Hematol 1994; 46: 18–23.
Ortu La Barbera EO, Chiusolo P, Laurenti L, Menichella G, Di Febo AL et al. MiCMA: an alternative treatment for refractory or recurrent Hodgkin's disease. Ann Oncol 2000; 11: 867–871.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–586.
Dixon DO, Mc Laughlin P, Hagemeister FB, Emil JF, Fuller LM, Cabanillas FF et al. Reporting outcomes in Hodgkin's disease and lymphoma. J Clin Oncol 1987; 5: 1670–1673.
Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and response criteria of the Estern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 569–573.
La Sala A, Dell’Olio M, Di Renzo N . MIPE vs. MJMA nella terapia di salvataggio del LNH aggressivo: studio prospettico, randomizzato del GISL. Riassunti del 35° Cong. Soc. Ital. Ematol. (Pavia, 10-13/9/1995). Edimes, Pavia, 1995; 297p.
Sorà F, Piccirillo N, Chiusolo P, Laurenti L, Marra R, Bartolozzi F et al. Mitoxantrone, carboplatin, cytosine arabinoside, and methylprednisolone followed by autologous peripheral blood stem cell transplantation. Cancer 2006; 106: 859–866.
Oyan B, Koc Y, Ozdemir E, Kars A, Turken A, Tekuzman G et al. Ifosfamide, idarubicin, and etoposide in relapsed/refractory Hodgkin disease and non-Hodgkin lymphomas: a salvage regimen with high response rates before autologous stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 688–697.
Zhou SY, Shi YK, He XH, Zhang P, Dong M, Huang DZ et al. Treatment effect of DICE regimen on patients with relapsed or refractory intermediate and high-grade non-Hodgkin's lymphoma. Ai Zheng 2005; 24: 465–469.
Clavio M, Garrone A, Pierri I, Michelis GL, Balocco M, Albarello A et al. Ifosfamide, epirubicin, etoposide (IEV) and autologous peripheral blood progenitor cell transplant: a feasible and effective salvage treatment for lymphoid malignancies. Oncol Rep 2005; 14: 933–940.
Müller-Beissenhirtz H, Kasper C, Nückel H, Dührsen U . Gemcitabine, vinorelbine and prednisone for refractory or relapsed aggressive lymphoma, result of a phase II single center study. Ann Hematol 2005; 84: 796–801.
Mey UJ, Orlopp KS, Flieger D, Strehl JW, Ho AD, Hensel M et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest 2006; 24: 593–600.
Atta J, Chow KU, Weidmann E, Mitrou PS, Hoelzer D, Martin H . Dexa-BEAM as salvage therapy in patients with primary refractory aggressive non-Hodgkin lymphoma. Leuk Lymphoma 2007; 48: 349–356.
Hertzberg MS, Crombie C, Benson W, Taper J, Gottlieb D, Bradstock KF . Outpatient fractionated ifosfamide, carboplatin, and etoposide as salvage therapy in relapsed and refractory non-Hodgkin's lymphoma. Ann Oncol 2006; 17 (Suppl 4): 25–30.
Simpson L, Ansell SM, Colgan JP, Habermann TM, Inwards DJ, Ristow KM et al. Effectiveness of second line salvage chemotherapy with ifosfamide, carboplatin and etoposide in patients with relapsed diffuse large B-cell lymphoma not responding to cisplatinum, cytosine arabinoside, and dexamethasone. Leuk Lymphoma 2007; 48: 1332–1337.
Park SH, Kim S, Ko OB, Koo JE, Lee D, Jeong YP et al. ESHAP salvage therapy for refractory and relapsed non-Hodgkin's lymphoma: a single center experience. Korean J Intern Med 2006; 21: 159–164.
Di Renzo N, Brugiatelli M, Montanini A, Vigliotti ML, Cernetti G, Liberati AM et al. Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) as salvage therapy in relapsed or refractorry aggressive non-Hodgkin's lymphoma: results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi. Leuk Lymphoma 2006; 47: 473–479.
Corazzelli G, Russo F, Capobianco G, Marcacci G, Della Cioppa P, Pinto A . Gemcitabine, ifosfamide, oxaliplatin and rituximab (R-GIFOX), a new effective cytoreductive/mobilizing slvage regimen for relapsed and refractory aggressive non-Hodgkin's lymphoma: results of a pilot study. Ann Oncol 2006; 17 (Suppl 4): 18–24.
Lòpez A, Gutierrez A, Palacios A, Blancas I, Navarrete M, Morey M et al. GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol 2007; 80: 127–132.
Sirohi B, Cunningham D, Norman A, Last K, Chau I, Horwich A et al. Gemcitabine, cisplatin and methylprednisolone (GEM-P) with or without rituximab in relapsed and refractory patients with diffuse large B-cell lymphoma. Hematology 2007; 12: 149–153.
Santoro A, Magagnoli M, Spina M, Pinotti G, Siracusano L, Michieli M et al. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin's lymphoma. Haematologica 2007; 92: 35–41.
Oki Y, Pro B, Fayad LE, Romaguera J, Samaniego F, Hagemeister F et al. Phase 2 study of gemcitabine in combination with rituximab in patients with recurrent or refractory Hodgkin lymphoma. Cancer 2008; 112: 831–836.
We are indebted to Dr Rachel Stenner for her careful revision of the English of this paper. Research was supported in part by grants from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica, Roma, from the Fondazione IRCCS Policlinico S Matteo, Pavia, and from the ‘Ferrata-Storti Foundation’, Pavia, Italy.
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Gobbi, P., Valentino, F., Lambelet, P. et al. Shortened and intensified MJMA: an effective salvage therapy for relapsed and refractory lymphomas and a strong mobilizer of PBSCs. Bone Marrow Transplant 44, 19–25 (2009). https://doi.org/10.1038/bmt.2008.421
- salvage chemotherapy
- Hodgkin's lymphoma
- non-Hodgkin's lymphoma
- marrow transplantation
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