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Highdose chemotherapy in relapsed or refractory hodgkin lymphoma patients: a reappraisal of prognostic factorsHematological OncologyHematol Oncol (2012)Published online in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/hon.2014 Original Research Article High-dose chemotherapy in relapsed or refractory Hodgkinlymphoma patients: a reappraisal of prognostic factors E Cocorocchio1*, F Peccatori1, A Vanazzi1, G Piperno2, L Calabrese1, E Botteri3, L Travaini4, L Preda5 and G Martinelli11Haematoncology Division, European Institute of Oncology, Milan, Italy 2Radiotherapy Division, European Institute of Oncology, Milan, Italy 3Epidemiology and Biostatistics Division, European Institute of Oncology, Milan, Italy 4Nuclear Medicine Division, European Institute of Oncology, Milan, Italy 5Radiology Division, European Institute of Oncology, Milan, Italy *Correspondence to: Emilia Cocorocchio, MD,Haematoncology Division, Istituto High-dose chemotherapy (HDCT) has a consolidated role in the treatment of patients with Europeo di Oncologia, Via refractory or relapsed Hodgkin lymphoma (HL). We report clinical results of 97 HL patients Ripamonti, 435, 20141 Milan, Italy.
who underwent HDCT for refractory (62 patients) or relapsed (35 patients) diseases in Istituto Europeo di Oncologia, from 1995 to 2009. Treatment included high-dose busulphan,etoposide, cytarabine and melphalan in 84 patients and high-dose idarubicin and melphalanin 13 patients with subsequent peripheral hemopoietic stem cells transplant. Outcomes wereevaluated in terms of progression-free survival (PFS) and overall survival (OS). In order toidentify prognostic factors for outcome, a multivariate analysis for age, sex, disease status(refractory/relapsed), disease stage, B symptoms, presence of extranodal involvement, bulkydisease, elevated lactate dehydrogenase, number of previous chemotherapy lines, remissionstatus before transplant, 18F-ﬂuoro-deoxy-D-glucose positron emission tomography(18FDG-PET) status before and after transplant was done. A clinical response was achievedin 91% of patients, with complete remissions in 76/97 patients. With a median follow-up of45 months (range 1–164 months), 5-year PFS and OS were 64% and 71%, respectively.
Remission status after induction therapy, 18F-ﬂuoro-deoxy-D-glucose positron emissiontomography status before and after transplant were the most important prognostic factorsfor PFS and OS in univariate or multivariate analyses. HDCT is able to induce a high Received 13 October 2011 remission rate and a prolonged PFS in more than 50% of the patients with refractory and Revised 5 March 2012 relapsed HL. Copyright 2012 John Wiley & Sons, Ltd.
Accepted 12 March 2012 Hodgkin lymphoma; high-dose chemotherapy; autologous transplant did not show a clear impact on outcome . However,there is a general agreement on disease chemosensitivity Deﬁnitive cure can be achieved after ﬁrst-line treatment in correlating with survival .
more than 70% of Hodgkin lymphoma (HL) patients. In More recently, 18FDG-PET has been used in HL, either refractory or relapsed disease, standard-dose regimens for staging or for assessing response . Early interim had demonstrated poor efﬁcacy, whereas high-dose 18FDG-PET is also an independent prognostic factor in chemotherapy (HDCT) followed by autologous stem cell newly diagnosed HL patients , but its impact in the support improved both progression-free survival (PFS) transplant setting, both before  and after transplant and overall survival (OS) [1–3]. The addition of peripheral , is still under investigation. Some data suggest that blood stem cells to HDCT reduced treatment-related 18FDG-PET status before transplant correlates with better morbidity and mortality. This strategy proved to be able disease-free survival , whereas others report a beneﬁt to cure about 50% of patients [1,4] and as a result became also in OS .
the standard therapeutic option.
We report the clinical results of 97 HL patients who To identify patients who can really beneﬁt from this underwent HDCT for refractory-relapsed HL in a single therapy, we evaluated several prognostic factors of outcome.
institution in the past 15 years, with correlation between In some retrospective analyses, the number of previous pre-transplant prognostic factors and outcome.
chemotherapy lines [5,6], chemosensitivity of relapse [6,7]and remission status before transplant [7,8] correlated withbetter results in terms of both failure-free survival and overallsurvival. The Hasenclever index, commonly used as a Patients and methods prognostic tool for newly diagnosed HL patients ,maintained its value also in this patient setting . On the We retrospectively analysed the data of 97 consecutive HL contrary, other factors such as the presence of systemic patients who had been administered with HDCT with stem symptoms at relapse , advanced stage  and age  cell transplants from 1995 to 2009 at the Istituto Europeo Copyright 2012 John Wiley & Sons, Ltd.
E Cocorocchio et al.
di Oncologia. The procedure was performed on 62 primary refractory and on 35 relapsed patients. Refractory patients cisplatin)  and G-CSF in 24 patients and after ICE (ifos- were deﬁned as patients obtaining less than a complete famide, carboplatin, etoposide)  or IGEV (ifosfamide, remission within 3 months from the end of ﬁrst-line gemcitabine, etoposide, vinorelbine)  and G-CSF in 9 chemotherapy, whereas relapsed patients were those who patients. Finally, one patient who had failed peripheral stem relapsed after at least 3 months of complete remission (CR) cell mobilization underwent bone marrow harvesting.
after ﬁrst-line chemotherapy. All patients were staged before Induction therapy with ESHAP for one-to-three cycles transplant and re-evaluated after transplant by means of was used in 73 patients, whereas IGEV for one-to-four computed tomography (CT) scans of the neck, chest, cycles was used in 16 patients. Eight patients received abdomen and pelvis, bone marrow biopsy, blood count and other programmes (DHAP, sequential HDCT). Thirteen chemistry evaluation (including total proteins, albumin, patients did not obtain complete or partial remission with potassium, sodium, calcium, glucose, urea, creatinine, total ﬁrst-line induction therapy and were shifted to other serum bilirubin, aspartate transaminase, alanine amino- regimens before transplant (e.g. from ESHAP to IGEV).
transferase, alkaline phosphatase, lactate dehydrogenase, Conditioning regimens before transplantation varied erythrocyte sedimentation rate, B2-microglobulin), when during the years: high-dose idarubicin + melphalan  was the treatment of choice until 2000 (13 patients). There- Responses were assessed or reviewed according to the after, patients were treated with busulphan, etoposide, Cheson criteria , because 18FDG-PET scan was routinely cytarabine and melphalan  (84 patients). 2 106 introduced for staging and response evaluation since 2003.
CD34+ cells/kg of body weight was considered necessary Overall, 41 patients underwent 18FDG-PET scan before to perform the procedure. Consolidation RT was performed transplant and 78 patients after transplant. 76% of 18FDG- on 18 patients.
PET–CT scans were performed at the Istituto Europeo diOncologia and were evaluated according to the Gallaminicriteria . All 18FDG-PET scans performed before 2007 or deemed positive elsewhere were internally revised andre-evaluated according to the same criteria.
Overall survival was deﬁned as the time from the date of During follow-up, physical examinations and biochem- diagnosis of refractory/relapsed disease to death or to the istry workup were performed every 3 months for the ﬁrst date of last follow-up in case of censored observations.
2 years, then every 6 months for the following 3 years and PFS was deﬁned as the time from the date of diagnosis to annually thereafter up to disease progression or death of progression or death from any cause, whichever occurred patients. Radiological evaluation was performed by CT ﬁrst. The date of the last visit date was used in the case of scan every 6 months for 5 years, annually thereafter for ﬁve censored observations. Age, sex, refractory/relapsed disease, stage, B symptoms, presence of extranodal involvement, Adverse events were assessed according to the Common bulky disease, elevated lactate dehydrogenase, number Terminology Criteria of the National Cancer Institute of previous chemotherapy lines, disease status before (NCI, version 3.0).
transplant, and 18FDG-PET status before and after transplant This review was notiﬁed to and approved by the institu- were evaluated to predict outcomes. Survival curves were tional review board. All procedures were followed in estimated using the Kaplan–Meier method, and the log-rank accordance with the Helsinki Declaration of 1975 (revised test was used to assess survival differences between groups in the univariate analysis. The Cox proportional hazard Before HDCT, 67 of 97 patients (69%) received at least regression model was used for the multivariate survival one line of chemotherapy and 30 (31%) received two or analysis, and the hazard ratio was calculated with a 95% more lines of chemotherapy. Radiotherapy (RT) was conﬁdence interval. In the multivariable analysis, we performed in combination with standard chemotherapy in adjusted the estimates of interest by age and sex, regardless 44 patients. Up front chemotherapy consisted of hybrid of their statistical signiﬁcance, and when possible by the chemotherapy regimens such as ChlVPP/ABVVP (chloram- Ann Arbor stage, that was the only variable that remained bucil, vinblastine, procarbazine, prednisone, Adriamycin, statistically signiﬁcant in some multivariable models bleomycin, vincristine, etoposide)  or MOPP/ABVD (p < 0.05). Following the rule of the thumb proposed by (mechlorethamine, vincristine, procarbazine, prednisone, Harrel et al.  who suggested to use no more than m/10 Adriamycin, bleomycin, vinblastine, dacarbazine)  in variables in the multiple regression model, m being the 34 patients, whereas 37 patients received ABVD  and number of events observed, we did not perform the multivar- 11 patients received VBM (vinblastine, bleomycin, metho- iable analysis when the number of events was too small (i.e.
trexate) . The remaining patients received other therapies around 10). All analyses were performed using the SAS such as MOPP .
software (SAS Institute, Cary, NC).
Mobilization, induction (salvage) and conditioning regi- mens were dependent on previous lines of chemotherapy,responses to treatments and time to relapse.
Peripheral stem cells were harvested after high-dose (4–7 g/m2) and granulcyte-colony Patients' characteristics are reported in Table 1. After stimulating factors (G-CSF)  in 63 patients, after conditioning chemotherapy, patients received a median Copyright 2012 John Wiley & Sons, Ltd.
Hematol Oncol (2012) HDCT in relapsed/refractory Hodgkin lymphoma developed acute myeloid leukaemia 2 years after transplant and died during induction therapy.
Four patients developed solid tumours: one colon adeno- carcinoma, one thyroid papillary carcinoma, one mela- noma and one solid tumour not otherwise speciﬁed, at 79, 6, 11 and 87 months after transplant, respectively. All Early (≤1 year) patients but one are alive and disease free.
Late (>1 year) All cases were evaluable for response. After induction therapy, 27 patients obtained CR, 12 unconﬁrmed CR (CRu), 51 partial remission (PR) and 7 stable disease (SD) or progressive disease (PD). After transplant, 64 patients obtained CR, 12 CRu, 13 PR, and 8 SD or PD (Table 2). All CRu patients were converted into CR. We Extranodal involvement* considered 34 patients as treatment failures: 13 cases who progressed after CR and 21 patients who did not achieve CR after transplant. Those patients received allogeneic bone marrow transplant in 11 cases (10 from sibling donors and one from an unrelated donor), whereas 23 Pre-transplant chemotherapy lines patients received other chemotherapy and/or RT or supportive care only. Twenty-eight patients died, in most Pre-transplant disease status cases (23) because of HL; other causes of death were allogeneic bone marrow transplant toxicity (three patients), secondary acute myeloid leukaemia (one patient) and secondary solid tumour (one patient). With a median CR, complete response; CRu, complete response uncorﬁrmed; PR, follow-up of 45 months (range 1–164 months), 5-year partial response; SD, stable disease; PD, progressive disease; LDH, PFS and OS were 64% and 71%, respectively.
Disease status after induction therapy was the most impor- *Information is not available on all patients.
tant prognostic factor for PFS and OS both in univariate(Table 3) and in multivariate analyses: in fact, 5-year PFS was amount of 3.2 106 CD 34+ cells/kg of body weight.
81%, 56% and 29% for patients with CR, PR and SD/PD, Engraftment was observed in all patients, with a median respectively (Figure 1), with an HR for patients in CR time to absolute neutrophils count > 1000/mL of 11 days corrected for age, sex and stage of 0.40 (95% CI 0.22–0.73; (range 9–23) and platelet count > 20 000/mL of 12 days p-value: 0.035); 5-year OS was 85%, 65% and 43% for (range 6–28). Most patients required transfusional support: patients with CR, PR and SD/PD, respectively (log-rank 92% of patients received a median of four red blood cell p-value: 0.01) with an HR for patients in CR corrected for unit transfusions (range 1–10) and 96% received two plate- age, sex and stage of 0.66 (95% CI 0.44–0.98 p-value: 0.02; let units (range 1–6).
Figure 2). Similar outcomes in terms of PFS and OS were Forty-one patients (42%) developed infections, mainly seen in patients with CR/CRu and PR before transplant (data bacteremia (25 patients) and pneumonia (9 patients), not shown). Also, the type of conditioning regimen used (data whereas fever of unknown origin was observed in 29 not shown) was not signiﬁcantly correlated with outcome.
patients. No early transplant-related mortality was observed.
The efﬁcacy of HDCT is evident for both refractory Two patients developed autoimmune thrombocytopenia 3 disease patients and for relapsed patients, with 5-year and 7 years following transplant. Another patient developed PFS of 66% and 60% and with 5-year OS of 72% and severe heart failure with mitral stenosis, transient myocardial 68%, respectively (Table 3). Among relapsed patients, no ischemia, inter-ventricular coronary stenosis and depressed signiﬁcant difference was found between18 early (within ejection fraction, 4 years after transplant. That patient 1 year from CR) or 17 late (after 1 year) relapsed patients received an anthracycline-containing regimen followed by (data not shown). The role of 18FDG-PET in predicting mantle RT (40 Gy) as ﬁrst-line treatment. Another patient outcome was evaluated before and after transplant.
Table 2. Comparison between pre-transplant and post-transplant clinical response Row percentage in brackets. CR, complete response; CRu, complete response uncorﬁrmed; PR, partial response; SD, stable disease; PD,progressive disease.
Copyright 2012 John Wiley & Sons, Ltd.
Hematol Oncol (2012) E Cocorocchio et al.
Table 3. Univariate survival analysis according to clinicopathological features before and after high-dose chemotherapy Events (5-year survival %) p-value Events (5-year survival %) p-value Extranodal involvement Pre-transplant chemotherapy lines One Pre-transplant PET Post-transplant PET Pre-transplant disease status Progression-free survival (PFS) and overall survival (OS) were compared among groups by means of the log-rank test. LDH, lactate dehy-drogenase; PET, positron emission tomography; CR/CRu, complete response/complete response uncorﬁrmed; PR, partial response; SD–PD, stable disease–progressive disease.
†Testing ≤35 vs. >35 years.
††Testing IV vs. I–II–III.
Complete Response Complete Response Partial Response Partial Response Stable disease and Stable disease and Progressive disease Progressive disease Log-rank test p-value: <0.01 Log-rank test p-value: <0.01 : 0.6 (95% CI 0.2-1.5) : 0.5 (95% CI 0.2-1.1) : 0.1 (95% CI 0.04-0.5) CR vs. SD/PD : 0.2 (95% CI 0.1-0.5) CR vs. SD/PD *Adjusted by age, sex and Ann Arbor Stage Years from transplant
*Adjusted by age, sex and Ann Arbor Stage Years from transplant
Figure 1. Progression-free survival according to pre-transplant Figure 2. Overall survival according to pre-transplant response Pre-transplant 18FDG-PET was available for 40 patients.
PFS for patients with negative and positive 18FDG-PET Five-year PFS among patients with negative 18FDG-PET was 86% and 22%, respectively (log-rank test p-value: was 79%, whereas among patients with positive 18FDG- <0.01; Figure 4), whereas 5 years OS for patients with PET, it was 43%. That difference was statistically signiﬁcant negative and positive 18FDG-PET was 92% and 43%, (log-rank test p-value: <0.01; Figure 3). Five-year OS respectively (log-rank test p-value: <0.01; Table 3).
among patients with negative 18FDG-PET was 92%, No signiﬁcant difference in terms of PFS and OS was whereas among patients with positive, 18FDG-PET it was observed between groups of patients who had undergone 43% (log-rank test p-value: <0.01; Table 3). 18FDG-PET 18FDG-PET scan before transplant and those who had status after transplant was available for 78 patients. Five-year not (data not shown).
Copyright 2012 John Wiley & Sons, Ltd.
Hematol Oncol (2012) HDCT in relapsed/refractory Hodgkin lymphoma and lung cancers, have emerged as the most signi late-onset secondary malignancies . In this series, Negative PET (n=26) solid tumours were recorded in four cases: one colon adenocarcinoma, one thyroid papillary carcinoma, one melanoma and one solid tumour not otherwise speci- ﬁed. Two patients received HDCT for their ﬁrst relapse, one for the second relapse and another for pri- Positive PET (n=14) mary refractory HL. It is not clear whether there is a cor- relation between the radiotherapy–chemotherapy delivered Log-rank test p-value: <0.01 and secondary malignancies. In patients who had received HR pos vs neg: 2.6 (95% CI 1.5-4.5) RT, the secondary cancer developed out of the RT ﬁeld.
Years from transplant
One case of acute leukaemia was observed in a patient, who had been heavily pretreated and who received two Figure 3. Progression-free survival in patients who underwent autologous transplants and RT for relapsed HL. Severe PET before transplant cardiac events are related to cumulative therapy burden,mainly because of the use of cardiotoxic drugs andRT . We report one case of severe cardiac failure after standard chemotherapy, HDCT and RT. It is well known that anthracyclines, as well as high-dose cyclophospha- mide, can induce heart failure, also independently of Negative PET (n=60) the total dose. This damage can be synergic with that caused by mediastinal RT. Anyway, the incidence in HL survivors seems to be in decline, probably thanks to the less-dose intensive RT , delivered mainly on the involved sites.
We conﬁrm that HDCT is able to induce a high Positive PET (n=18) remission rate and a prolonged PFS in more than 50% of Log-rank test p-value: <0.01 patients with either refractory or relapsed HL. Refractory HR* pos vs neg: 7.6 (95% CI 3.3-17.0) * Adjusted by age and sex Years from transplant
and relapsed status does not seem to in ﬂuence either PFS or OS. As a matter of fact, the outcome of patients withrefractory disease who are responsive to induction therapy Figure 4. Progression-free survival in patients who underwent is superimposable to that of patients with relapsed disease PET after transplant responsive to induction therapy (data not shown). So,chemosensitivity to induction therapy is the most important prognostic factor of outcome both in univariate and inmultivariate analyses.
Our experience conﬁrms the elective role of HDCT 18FDG-PET status before transplant is suggested to followed by autologous stem cell transplant in the be able to predict outcome . In our series, pre- treatment of refractory and relapsed HL patients, which transplant negative 18FDG-PET identiﬁed patients with was evident throughout the observation time. The better outcomes and was a useful prognostic factor.
improvement in supportive care and also a better selec- The difference in PFS is also signiﬁcantly better tion of patients made this procedure safe and manage- in patients with negative 18FDG-PET after transplant able, with a considerable decrease in mortality rate in (p < 0.001). Thus, it seems that 18FDG-PET evaluation recent years .
before and after transplant is useful in identifying The best induction chemotherapy and its duration are patients who are more likely to beneﬁt from autologous controversial, mainly because of the risk of long-term toxicity, such as secondary malignancies or severe/fatal Patients who failed to achieve cure with autologous cardiac events. Much depends on previous chemotherapies transplant still have a poor prognosis, and alternative and on clinical responses. The goal is achieving the best strategies should be considered. The use of monoclonal possible remission before transplant. ESHAP or IGEV antibodies alone, such as rituximab  or conjugated, chemotherapy regimens are both effective against lym- such as brentuximab vedotin , is under investiga- phoma and as mobilization therapies and allow to avoid tion, whereas allogeneic transplant with reduced condi- the use of high-dose cyclophosphamide for stem cell tioning regimen seems to be effective , although the mortality rate still makes this option controversial.
Secondary malignancies, myelodysplastic syndromes and More recently, new agents such as histone deacetilates cardiac events represent the main cause of excess mortality inhibitors (panobinostat) , lenalidomide  and in HL survivors, correlated with the whole chemotherapy everolimus  have been introduced in HL management and RT burden . The use of alkylating agents and and are under evaluation. They may play a role in com- etoposide is associated with an increased risk of early onset bination with chemotherapy or as maintenance therapy in acute leukaemias, whereas solid tumours, mainly breast future HL treatment strategies.
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Hematol Oncol (2012) E Cocorocchio et al.
Conﬂict of interest 16. Crocchiolo R, Canevari C, Assanelli A, et al. Pre-transplant 18FDG-PET predicts outcome in lymphoma patients treated withhigh-dose sequential chemotherapy followed by autologous stem The authors state that there is no conﬂict of interest.
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TO APPEAR IN THE ASTROPHYSICAL JOURNALPreprint typeset using LATEX style emulateapj v. 8/13/10 ELEMENTAL ABUNDANCES OF SOLAR SIBLING CANDIDATES I. RAM´IREZ1 , A. T. BAJKOVA2 , V. V. BOBYLEV2,3 , I. U. ROEDERER4 , D. L. LAMBERT1 , M. ENDL1 , W. D. COCHRAN1 , P. J. MACQUEEN1 , AND R. A. WITTENMYER5,6 To appear in the Astrophysical Journal Dynamical information along with survey data on metallicity and in some cases age have been used recently