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Thiotepa, Etoposide, Cyclophosphamide, Cytarabine, and Melphalan (TECAM) Conditioning Regimen for Autologous Stem Cell Transplantation in Lymphoma
Accepted Manuscript Thiotepa, Etoposide, Cyclophosphamide, ARA-C and Melphalan (TECAM) conditioning regimen for autologous stem cell transplantation in lymphoma Sigal Grisariu, Michael Y. Shapira, Reuven Or, Batia Avni PII:
S2152-2650(17)31849-9
DOI:
10.1016/j.clml.2018.02.008
Reference:
CLML 1068
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 19 November 2017 Revised Date:
16 January 2018
Accepted Date: 10 February 2018
Please cite this article as: Grisariu S, Shapira MY, Or R, Avni B, Thiotepa, Etoposide, Cyclophosphamide, ARA-C and Melphalan (TECAM) conditioning regimen for autologous stem cell transplantation in lymphoma, Clinical Lymphoma, Myeloma and Leukemia (2018), doi: 10.1016/ j.clml.2018.02.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Thiotepa, Etoposide, Cyclophosphamide, ARA-C and Melphalan (TECAM) ACCEPTED MANUSCRIPT conditioning regimen for autologous stem cell transplantation in lymphoma. Sigal Grisariu1, Michael Y Shapira1, Reuven Or1, Batia Avni1 Hadassah-Hebrew University Medical Center, Bone Marrow Transplantation and Cancer Immunotherapy Department, Jerusalem, Israel1
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Corresponding Author: Batia Avni, M.D. Current Address: Hadassah Medical Center Department of Bone Marrow Transplantation
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POB 12000 Jerusalem 91120
Phone: 972-2-6776561 Fax: 972-2-6776561
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Email: [email protected]
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Israel
Running Title: TECAM conditioning regimen for stem cell transplantation
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Keywords: TECAM, Conditioning regimen, autologous stem cell transplantation, lymphoma
Conflict of interest: The authors have nothing to disclose.
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Abstract
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High dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for relapsed non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Conditioning regimens with high dose BCNU are associated with Idiopathic Pneumonitis Syndrome (IPS). We therefore created a modified alternative TECAM conditioning regimen,
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consisting of etoposide, thiotepa, cytarabine, cyclophosphamide and melphalan. We
retrospectively analyzed our cohort of NHL and HL patients, who underwent ASCT with the TECAM conditioning between 2000 and 2013. Two hundred and twelve patients were
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analyzed. While toxicity and engraftment were analyzed on all 212 patients, survival analysis was done on the two largest groups of patients, those with Diffuse Large B Cell Lymphoma
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(DLBCL) and Hodgkin’s Lymphoma (N=127 ) in order to minimize heterogeneity. Three year overall survival among DLBCL and HL patients was found to be 0.618 (95% CI 0.490-0.722) and 0.828 (95% CI 0.701-0.904), respectively. Stage IV disease at transplantation, was found to be a statistically significant poor prognostic factor. Higher ECOG performance status and
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progressive disease at transplantation were found to be borderline significant. No IPS cases were reported in our cohort. Six patients died due to treatment related toxicity during the first 100 days. Three-year PFS was found to be 0.5 (95% CI 0.37-0.61) for HL patients and
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0.49 (95% CI 0.36-0.60) for DLBCL patients. Our results are encouraging and justify evaluation of TECAM versus BEAM in a prospective multicenter study in a large homogenous
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patient population.
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Introduction
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High dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for chemosensitive relapsed non Hodgkin lymphoma (NHL) and Hodgkin lymphoma 1, 2. Initial prospective studies compared chemotherapy plus radiotherapy to radiotherapy plus high dose chemotherapy and ASCT. At five years, the rate of event-free
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survival was 46 percent in the transplantation group and 12 percent in the group receiving chemotherapy without transplantation , and the rate of overall survival was 53 and 32
percent, respectively 3. Friedberg et al reported secondary myelodysplastic syndrome
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(MDS) in 7.4% of patients at 47 months and 19.8% at ten years in 552 patients who
underwent ASCT for NHL, with a uniform ablative regimen of cyclophosphamide and total
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body irradiation (TBI) 4. Due to this serious complication, most transplant centers moved away from TBI containing regimens towards chemotherapy based regimens. Currently, the choice of conditioning regimen varies and is typically based on institutional experience. In most centers, CBV (Cyclophosphamide, Carmustine (BCNU), and Etoposide ) or BEAM
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(carmustine, etoposide, cytarabine, and melphalan ) regimens are the conditioning regimens of choice for patients undergoing ASCT. High dose BCNU and TBI based conditioning regimens with ASCT have been associated with Idiopathic Pneumonitis syndrome (IPS),
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causing significant morbidity and mortality. The occurrence of IPS after CBV or TBI based regimens was reported in 6% and 5% of patients, respectively. The incidence of IPS, one
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year after ASCT with BEAM as the conditioning regimen was reported to be around 3% 5 . Relapsed or refractory non Hodgkin lymphoma (NHL) patients conditioned with BEAM were reported to achieve a complete remission at one month of 62.8%, with a median EFS and OS of 16.1 and 30.6 months, respectively 6. Relapsed or refractory Hodgkin lymphoma (HL) patients conditioned with BEAM were reported to achieve a median EFS and OS of 12 and 53 months, respectively 7. This high incidence of IPS, related mainly to the use of BCNU, and the relatively short EFS and OS has led many centers to create modified regimens, replacing
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carmustine with other agents as a strategy to both increase efficacy and reduce toxicities
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associated with the BEAM regimen. Due to its relative safety and a low-toxicity profile, thiotepa has been used in the context of stem cell transplantation for multiple myeloma, breast carcinoma, leukemia and lymphoma. In a leukemia animal model, it was shown that thiotepa has a synergistic or additive effect
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when combined with other agents. The activity of high dose cyclophosphamide in lymphoma patients is well established; the combination of thiotepa and
cyclophosphamide was as effective as the commonly used myeloablative combinations 8, 9.
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Recent reports have shown thiotepa based regimens to have similar efficacy and tolerability as the conventional BEAM regimen.10 The aim of our study was to report the long-term
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safety and efficacy of our TECAM conditioning protocol consisting of thiotepa, etoposide, cyclophosphamide, cytarabine and melphalan at Hadassah Medical Center.
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Patients and Methods:
Data for all patients are routinely collected at the bone marrow transplantation (BMT) department using a predefined case report form. Medical records and laboratory data were
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reviewed from time of referral to our center for lymphoma treatment until last follow up. We retrospectively analyzed our cohort of NHL and HL patients who underwent ASCT with
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the TECAM conditioning regimen, at the Hadassah medical center BMT department, between 2000 and 2013. At this time period, TECAM was the standard conditioning protocol used at our center.
Two hundred and twelve patients, 114 males and 98 females, were included. Seventy-four underwent ASCT for HL while 138 for NHL. The median follow up period was 2.84 years (max 13.38 years) from ASCT and 3.52 years for surviving patients. The TECAM conditioning protocol consisted of etoposide 200mg/m2 from day -6 to -3, thiotepa 40mg/m2 from day -5 4
to -2, cytarabine 200mg/m2 from day -4 to -1, cyclophosphamide 60mg/kg on day -3 and
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melphalan 60mg/m2 on day -2 and -1 . Doses were adjusted as follows: For patients between the ages of 40-50, doses were reduced by 0.5% per year. For patients older than 50 years, doses were reduced by 1% per year. For patients with BMI above 35 doses were adjusted for BMI of 35.
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the principles of the Helsinki Declaration (0053-16-HMO).
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The study was performed with institutional review board approval and in accordance with
Peripheral stem cell harvest
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Peripheral blood stem cells (PBSC) were mobilized by subcutaneous filgrastim (Neupogen, 5 µg/kg twice daily for 5 days) and mobilized PBSC were collected on days 5 and 6 (if needed).
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Supportive Care
Prior to transplantation, all patients received high dose trimethoprim/sulfamethoxazole until day −2, acyclovir from the initiation of therapy until day +120 and allopurinol until day −1.
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Trimethoprim/sulfamethoxazole was reinstituted for a period of 6 months after recovery from neutropenia. Febrile neutropenia was treated according to the hospital's infectious
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disease protocols.
Patients were treated in reverse isolation HEPA-filtered rooms, and received a regular diet. Additional supportive measures, such as analgesics, parenteral nutrition and blood component transfusions, were administered as necessary. Patients were treated with post transplant subcutaneous filgrastim 5 µg/kg/d starting from day +6 until stable engraftment of neutrophils.
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Assessment of engraftment and toxicity The time of leukocyte engraftment was defined to be the first of three consecutive days with
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an absolute neutrophil count (ANC) 0.5 x 109/L, and that of platelet engraftment was defined as the day that platelet count was > 20 x 109/L with no requirement of platelet transfusion. Veno-occlusive disease (VOD) was classified according to the Baltimore criteria and defined
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as severe when complicated by multiorgan failure11.Treatment-related mortality (TRM) was defined as any death after SCT not caused by relapse or disease progression within 100 days
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of transplantation. Overall survival (OS) was defined as time from the day of transplantation to death from any cause, or last follow-up. Relapse was defined as the recurrence of the hematological malignancy, after the initial achievement of complete remission. Three-year non-relapse mortality (NRM) was defined as any death without recurrent disease. Progression-free survival (PFS) was defined as the time from high dose chemotherapy with
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ASCT to either relapse or death which ever occurred first or at last contact. Due to the heterogeneity of the lymphoma subtypes, OS and PFS analysis were performed solely in the
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DLBCL and HL patient groups.
Definitions and statistical considerations The pre and post-transplant lymphoma status were classified according to the following criteria: Complete response (CR, absence of all clinical and radiographic evidence of disease), partial response (PR,> 50% reduction of the surface area of all measurable disease), stable disease (SD, <50% reduction of the surface area of all measurable disease) and progressive disease (PD, any progression of disease). 6
ACCEPTED MANUSCRIPT Descriptive statistics including counts and percentage for categorical variables, and mean, standard deviation (SD), median and range, and 95% confidence limits of the mean as appropriate were used for describing patients' characteristics.
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test was applied for comparing survival curves, using SAS 9.2.
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The Kaplan-Meier survival model was used for assessing survival curves, and the log-rank
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Results:
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Patients' characteristics Two hundred and twenty seven patients underwent ASCT with the TECAM conditioning protocol between the years 2000 to 2013. Fifteen patients were not included in the analysis
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due to lack of complete data. Two hundred and twelve patients were included in our cohort. Median age was 46.3 years (range: 16-71). Patients' characteristics prior to ASCT are summarized in table 1. One hundred and twenty seven patients received high dose
chemotherapy and ASCT for Hodgkin and diffuse large B cell lymphomas. Other lymphoma
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subtypes included: T cell, low grade transformed, follicular and mantle. The median number
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of treatment lines before ASCT was 2 (range: 1-7). One hundred and eighty patients (85%) were transplanted with responsive disease, of them 101 were in CR. The vast majority of patients in the HL and DLBCL groups were transplanted due to primary refractory or
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relapsed disease.
Hematopoietic engraftment and toxicity
Hematopoietic engraftment and toxicity details are summarized in table 2. The median time
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to recovery of absolute neutrophil count>0.5x109/L was 12 days and platelet count>20x109/L was 17 days. Three patients died before day +30 due to sepsis with no engraftment. One
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patient died from persistent disease with bone marrow involvement and no engraftment. Two patients failed to achieve platelet engraftment. Fifty percent of patients suffered from mucositis, 52% needed TPN support, 30% had an episode of bacteremia, 4.7% septic shock and 16% renal failure(defined as creatinine elevation >x1.5 from baseline) at any time point during hospitalization for transplantation. No patient developed severe VOD. Thiotepa related skin toxicity was not observed. The median number of hospitalization days was 26 (range 18-124). Eight patients (3.77%) died during the first 100 days. Causes of death were: 8
active disease in two patients, infection in four patients and multiorgan failure in two
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patients.
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Outcome and survival analysis To minimize heterogeneity of lymphoma subtypes, survival analysis were done on the two
largest lymphoma subgroups comprising the majority of patients: HL (74 patients) and DLBCL
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(73 patients). The overall survival of patient with DLBCL and HL is shown in Fig. 1. Three
years overall survival among DLBCL and HL patients was found to be 0.618 (95% CI 0.490-
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0.722) and 0.828 (95% CI 0.701-0.904), respectively (p = 0.0058). Pre-transplantation stage IV disease, was found to be a statistically significant bad prognostic factor (p=0.0002). Higher ECOG performance status and progressive disease at transplantation were found to be borderline significant (p=0.07). Age, dose reduction of conditioning protocol and number of
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treatment lines before ASCT, had no influence on survival (table 3). In contrast to the worse OS of patients in stage 4 disease at transplantation, we found no impact of disease stage on OS of patients in stages I to III. Three months post ASCT, 61.9% of patients were in CR, 4.1%
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in PR and 19.72% were found to be with progressive disease, 4.76% died during the first three months post ASCT and for 9.52% data was not available. In the HL group 66.2% were in
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CR and 8.1% were in PR, while in the DLBCL group 57.5% were in CR and 8.21% were in PR. Fifteen patients underwent planned consolidation with radiotherapy post ASCT and 26 patients received immunotherapy. Three-year PFS of 127 patients with DLBCL and HL is shown in Fig. 2. Three-year PFS was found to be 0.5 (95% CI 0.37-0.61) for HL patients and 0.49 (95% CI 0.36-0.60) for DLBCL patients. Three-year PFS for patients achieving CR after transplantation was significantly
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better (0.660- 95% CI 0.546-0.752) than for those who were in PR (0.33 - 95% CI 0.046-
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0.675) or in PD (0.00) with a P value of <0.0001 (table 4). Of the 127 patients with DLBCL and HD, 19 underwent allogeneic HSCT, of them five survived with a median follow up of 6 years.
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In the group of 212 transplanted lymphoma patients, with a maximal observation time of 13.38 years from ASCT, a second malignancy was diagnosed in 9 patients (4.24%): five had MDS or acute myeloid leukemia (AML), one developed peripheral T cell lymphoma and melanoma in situ, one renal cell carcinoma, one breast carcinoma and one epidermoid
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carcinoma of the parotid. Other reported late complications were: one patient developed
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avascular necrosis of the hip, and four patients suffered from recurrent infections (of these two had hypogammaglobulinemia). One patient experienced hepatitis B reactivation. No patient was reported to suffer from IPS.
Out of the 212 transplanted patients, 76 (35.8%) patients died during the observation period, of them in 61(80.26%) the cause of death was relapsed lymphoma. Six patients died
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due to transplant related toxicity, of them four died due to infection and two due to multiorgan failure. Six patients died from secondary malignancy (5 with MDS/AML and 1 from T
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cell lymphoma), one patient died from unrelated causes and two patients from unknown
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causes. The incidence of 3 year NRM was 2.8%.
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Discussion:
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High dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for chemo sensitive relapsed non Hodgkin lymphoma (NHL) and Hodgkin lymphoma. Currently, the choice of conditioning regimen varies and is typically based on institutional experience. In most centers, CBV or BEAM regimens are the conditioning
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regimens of choice for patients undergoing ASCT 6, 7, 12, 13. Due to concern of late toxicities, supply and cost issues for carmustine, carmustine is not an option in many centers. Alternative regimens such as etoposide and melphalan (VP16/MEL); gemcitabine,
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busulphan, and melphalan (GemBuMel); and busulfan, cyclophosphamide, etoposide
(BuCyE) are used at many institutions 14. Wang et al compared retrospectively 52 patients
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receiving CBV to 20 patients receiving BEAM as conditioning regimen in ASCT for NHL and HL. They showed a better OS (with a mean follow-up of 16 months) for patients receiving BEAM as compared to CBV (84 vs. 60% )13. Chen et al retrospectively studied 4917 patients who underwent ASCT comparing BEAM, CBV, BuCY and TBI containing regimens. For NHL
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patients, probability of three year OS were 64% for BEAM, 60% and 52% for CBV –BCNU low or high respectively, 49% for BuCy and 50% for TBI. For HL patients the probability of three year OS using the same conditioning regimens were 79%, 73%, 68%, 65% and 47%
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respectively5. Our results using the TECAM conditioning protocol are comparable to those reported for BEAM and CBV, showing the probability of overall survival among DLBCL and HL
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patients to be 0.618(95% CI 0.573-0.738) and 0.828(95% CI 0.701-0.904), respectively. Using TECAM as our conditioning regimen, we observed TRM and 3 year NRM in only 6 patients out of a cohort of 212 patients (2.83%). Chen et al reported a 1 year TRM incidence of 4% in the BEAM group and 7 and 8% in the CBV-BCNU low and high groups respectively 5. Puig et al compared TRM in 113 patients with NHL and HL undergoing ASCT. They reported a cumulative incidences of TRM of 25% in the CBV and 7% in the BEAM group 15. E Joffe et al 16
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recently reported a TRM of 1.6% using TECAM for 65 lymphoma patients. Our TRM results
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are comparable to those reported by others using BEAM or CBV or conditioning protocols. Our retrospective study shows a rate of 50% mucositis (of them 27.1% grade IV) and 52% of patients receiving TPN support. Our department policy in TPN support is not only related to high grade mucositis but also for patients with low intake due to other reasons (e.g. nausea,
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vomiting ect.). Although we report a high rate of TPN support, our mucositis rate is similar to the rate reported in other conditioning regimens. The EBMT lymphoma working party
reported in a retrospective study comparing BEAM to thiotepa based TEAM regimens, a
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mucositis rate of 60% in both groups correlating with many other similar reports10, 12, 13.
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High dose BCNU and TBI based regimens have been associated with Idiopathic Pneumonitis syndrome after ASCT, causing significant morbidity and mortality. Lane at al reported an incidence of IPS of 22% in 222 patients treated with high dose BCNU as part of CBV protocol at the Dana Farber Cancer Institute, with a median time to development of IPS being 50 days 17
. Chen et al reported an incidence of IPS by 1 year after ASCT to be 3% with BEAM and CBV
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(low) 4% for BuCy and 5% for TBI. In these patients, those who developed IPS had a significantly higher rate of TRM and shorter PFS and OS 5. In our cohort, none of the patients conditioned for ASCT with the TECAM protocol, suffered from clinical symptoms or
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laboratory proven IPS. Secondary malignancies have been reported to be the most common non relapse related cause of death in 9 out of 150 (6%) Hodgkins' patients treated with HDT-
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ASCT in the Norway national cohort 2. Goodman et al at the Memorial Sloan-Kettering Cancer Center reported second malignancies in 15 patients out of 153 Hodgkin patients who survived for more than 2 years after ASCT 18. Lenz et al in Germany reported an estimated 5year risk for secondary hematologic malignancy of 3.8%, in patients undergoing ASCT conditioned with TBI and cyclophosphamide for low grade lymphoma.19. The Nebraska Lymphoma Study Group (NLSG) reported on 2 year survivors after ASCT for Hodgkin lymphoma patients: they reported deaths from secondary malignancies in 10% of patients 12
receiving CBV and 5% in the BEAM group. We have reported a second malignancy in 9
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patients out of 212 (4.24%), of which 5(2.35%) had a secondary hematologic malignancy 20. Like others have shown, we report worse OS for patients with progressive disease or stage 4 disease at transplantation, emphasizing the importance of a chemo sensitive disease before ASCT. Interestingly, in our cohort, there was no difference in OS between stages 0 to III. This
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finding raises the question of the necessity to aim for CR before transplantation, with the cost of more chemotherapeutic lines. Larger cohorts are needed to address this question.
A retrospective comparison between TECAM and BEAM as conditioning regimens for high
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risk lymphoma patients was recently published. One hundred and twenty five patients were analyzed. Of them 65 received the TECAM protocol. The reported results are comparable to
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ours, even though the patients' cohort is significantly smaller and heterogeneous in terms of lymphoma subtypes. Like us, they conclude that TECAM has comparable efficacy and safety profile as BEAM and suggest an advantage using TECAM for older patients16. Our study limitations are those inherent in its retrospective design and the different
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proportions of patients with different lymphoma subtypes. In addition, we have reported our experience using TECAM for 13 years (between the years 2000 and 2013), a time span in which many new agents were added to the treatment of patients including mabthera,
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care21-24.
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brentuximab, new antibiotics and antifungal agents and development of a better supportive
With the limitations of a retrospective analysis we conclude that our TECAM
conditioning regimen shows similar efficacy to the commonly used BEAM protocol. The toxicity profile of TECAM was found to be similar to the BCNU containing regimens, excluding pulmonary fibrosis - a complication that is known to have a profoundly negative effect on overall survival and is related to high dose BCNU. Our results encourage considering TECAM as an alternative conditioning regimen for ASCT in high risk lymphoma
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patients. A Large prospective homogenous clinical trial designed to verify our results is
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warranted.
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Lenz G, Dreyling M, Schiegnitz E, Haferlach T, Hasford J, Unterhalt M et al. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 2004; 22(24): 4926-4933. e-pub ahead of print 2004/12/22; doi: 22/24/4926 [pii] 10.1200/JCO.2004.06.016
20.
William BM, Loberiza FR, Jr., Whalen V, Bierman PJ, Bociek RG, Vose JM et al. Impact of conditioning regimen on outcome of 2-year disease-free survivors of autologous stem cell transplantation for Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk; 13(4): 417-423. e-pub ahead of print 2013/06/19; doi: S2152-2650(13)00109-2 [pii] 10.1016/j.clml.2013.03.009
21.
Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H et al. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol; 168(6): 824-834. e-pub ahead of print 2014/12/30; doi: 10.1111/bjh.13234
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16.
22.
Pham A, Chen R. Brentuximab vedotin for the treatment of Hodgkin's lymphoma. Expert Rev Hematol; 8(4): 403-412. e-pub ahead of print 2015/05/15; doi: 10.1586/17474086.2015.1044432
23.
Isidori A, Clissa C, Loscocco F, Guiducci B, Barulli S, Malerba L et al. Advancement in high dose therapy and autologous stem cell rescue in lymphoma. World J Stem Cells; 7(7): 1039-1046. e-pub ahead of print 2015/09/04; doi: 10.4252/wjsc.v7.i7.1039
24.
Fernandez HF, Escalon MP, Pereira D, Lazarus HM. Autotransplant conditioning regimens for aggressive lymphoma: are we on the right road? Bone Marrow 16
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Transplant 2007; 40(6): 505-513. e-pub ahead of print 2007/06/26; doi: 1705744 ACCEPTED MANUSCRIPT [pii] 10.1038/sj.bmt.1705744
17
Table 1. Patients' characteristics prior to ASCT.
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Variable
N=212
Age(years)
114 (46%)
Male
98 (54%)
Female Type of lymphoma
53 (25%)
Hodgkin's
74 (34.9%)
T cell
23 (10.8%)
Low grade transformed to DLBCL
20 (9.4%) 15 (7.1%)
Mantle
14 (6.6%)
Follicular
13 (6.1%)
Other NHL ECOG performance status at ASCT
160 (75.5%)
0
34 (16%)
1
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4 (1.9%)
2
14 (6.6%)
Unknown Disease status at ASCT Complete Response
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Partial Response Stable Disease
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Diffuse large B cell
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Progressive Disease Unknown
101 (47.6%) 79 (37.3%) 4 (1.9%) 26 (12.3%) 2 (0.9%)
No. of treatment lines before ASCT Median (range)
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Gender
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46.3 (16-71)
Median (range)
2.0 (1-7)
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ACCEPTED MANUSCRIPT Table 2. Hematopoietic engraftment and toxicity.
absolute neutrophil count>500/mm3 (days) Median (Range) platelets count>20,000 (days)
12 (9-72)
Median (Range) No. of Hospitalization days Median (Range) Mucositis (No. of Patients,%) Grade I Grade II Grade III Grade IV Unknown No. of TPN days Median (Range) Infectious complications (No. of patients) Bacteremia Septic Shock Transplant related mortality No. of patients
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26 (18-124) 106 (50%) 24 (22.6%) 17 (16%) 21 (19.8%) 29 (27.3%) 15 (14.1%)
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17 (8-935)
2 (0-49)
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64 (30%) 10 (4.7%)
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6 (2.83%)
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ACCEPTED MANUSCRIPT Table 3. Univariate analysis of statistically significant parameters affecting 3-year overall
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survival.
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ACCEPTED MANUSCRIPT N=147
Event N (%)
3 years overall survival
95% CI
P value
DLBCL
73
26(35.62)
0.618
0.49-0.72
0.0013
HL
74
10(13.51)
0.829
0.70-0.90
0
69
16(23.2)
0.751
0.62-0.84
I
16
5(31.2)
0.628
0.32-0.83
II
36
3(8.3)
0.901
0.72-0.97
III
10
3(30.00)
0.700
IV
14
8(57.14)
0.283
UN
2
ECOG at entry to ASCT 110
22(20.0)
1
22
8(36.3)
2
3
2(66.7)
12
UN
0.63
0.39-0.73
0.33
0.00-0.66
4(33.3)
0.66
0.33-0.86
16(23.2)
0.75
0.62-0.84
11(18.97)
0.71
0.62-0.86
3
1(33.33)
0.50
0.006-0.91
17
8(47.06)
0.48
0.21-0.70
69
PR
58
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CR
PD
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Disease status at entry to ASCT
SD
0.06-0.55
0.75
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0
0.0002
0.33-0.89
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Stage at entry to ASCT
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Disease
0.0760
0.0721
3 month post ASCT disease status CR
91
7(7.69)
0.90
0.80-0.95
PR
6
1(16.67)
0.83
0.27-0.97
PD
29
19(65.5)
0.22
0.08-0.41
UN
14
0.73
0.38-0.91
3(21.43)
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<0.0001
Table 4. Univariate analysis of three-year Progression Free Survival (PFS).
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N=147
EVENT N (%)
3 YEAR PFS
95% CI
P VALUE
DLBCL
73
35 (47.95)
0.49
0.37-0.60
0.386
HL
74
33 (44.59)
0.50
0.37-0.61
0
110
48 (43.64)
0.50
0.40-0.60
1
22
11 (50.00)
0.50
0.28-0.68
2
3
2 (66.67)
0.33
0.00-0.77
12
7 (58.33)
0.42
0.15-0.66
0.45-0.69
Disease
ECOG at entry to ASCT
Disease status at entry to ASCT
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UN
69
27 (39.13)
0.58
PR
58
30 (51.72)
0.44
SD
3
1 (33.33)
0.50
PD
17
10 (58.82)
0.34
CR
91
28 (30.77)
0.66
0.57-0.74
PR
6
4 (66.67)
0.33
0.08-0.63
PD
29
27(93.10)
0.00
0.000
UN
14
3 (21.43)
0.75
0.41-0.91
17 (34.69)
0.62
0.46-0.74
4 (66.67)
0.33
0.04-0.67
11 (91.67)
0.00
0(0.00)
0.642
0.71
0.54-0.82
49
PR
6
PD
12
UN
6
0.30-0.56
0.006-0.91 0.11-0.58
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3 month disease status DLBCL
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CR
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3 Month disease status HL
CR
42
11 (26.19)
PR
7
0 (0.00)
PD
17
16(94.12)
0.05
0.00-0.23
UN
8
3(38.46)
0.62
0.23-0.86
22
0.2226
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CR
3 month post ASCT disease status
0.4722
<0.0001
<0.0001
<0.0001
Figures Legends:
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Fig.1: Ten-year overall survival curves by disease group.
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Fig.2 Ten-year event free survival curves by disease group.
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ACCEPTED MANUSCRIPT Fig.1: Ten year overall survival curves by disease group.
Overall Survival (Kaplan Meier)
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0.8
0.6
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Survival Distribution Function Estimate
1.0
0
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0.4
6
4
2
time (years)
DX Log-rank p-value=0.0029
HD
DLBCL+Transformed
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HD: Hodgkin's disease; DLBCL: diffuse large B cell lymphoma
8
10
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Fig.2 Ten year event free survival curves by disease group. Event free survival free (kaplan Meier) Progression Survival (Kaplan Meier)
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1.0
SC
0.6
0.4
0.2 0
2
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Survival Distribution Function Estimate
0.8
4
6
8
time (years)
DX
HD -----------DLBCL+Transformed HD DLBCL
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Log-rank p-value=0.1843
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EFS: event free Survival; HD: Hodgkin's disease; DLBCL: diffuse large B cell lymphoma
10
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S2152-2650(17)31849-9
DOI:
10.1016/j.clml.2018.02.008
Reference:
CLML 1068
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 19 November 2017 Revised Date:
16 January 2018
Accepted Date: 10 February 2018
Please cite this article as: Grisariu S, Shapira MY, Or R, Avni B, Thiotepa, Etoposide, Cyclophosphamide, ARA-C and Melphalan (TECAM) conditioning regimen for autologous stem cell transplantation in lymphoma, Clinical Lymphoma, Myeloma and Leukemia (2018), doi: 10.1016/ j.clml.2018.02.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Thiotepa, Etoposide, Cyclophosphamide, ARA-C and Melphalan (TECAM) ACCEPTED MANUSCRIPT conditioning regimen for autologous stem cell transplantation in lymphoma. Sigal Grisariu1, Michael Y Shapira1, Reuven Or1, Batia Avni1 Hadassah-Hebrew University Medical Center, Bone Marrow Transplantation and Cancer Immunotherapy Department, Jerusalem, Israel1
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Corresponding Author: Batia Avni, M.D. Current Address: Hadassah Medical Center Department of Bone Marrow Transplantation
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POB 12000 Jerusalem 91120
Phone: 972-2-6776561 Fax: 972-2-6776561
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Email: [email protected]
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Israel
Running Title: TECAM conditioning regimen for stem cell transplantation
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Keywords: TECAM, Conditioning regimen, autologous stem cell transplantation, lymphoma
Conflict of interest: The authors have nothing to disclose.
1
Abstract
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High dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for relapsed non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Conditioning regimens with high dose BCNU are associated with Idiopathic Pneumonitis Syndrome (IPS). We therefore created a modified alternative TECAM conditioning regimen,
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consisting of etoposide, thiotepa, cytarabine, cyclophosphamide and melphalan. We
retrospectively analyzed our cohort of NHL and HL patients, who underwent ASCT with the TECAM conditioning between 2000 and 2013. Two hundred and twelve patients were
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analyzed. While toxicity and engraftment were analyzed on all 212 patients, survival analysis was done on the two largest groups of patients, those with Diffuse Large B Cell Lymphoma
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(DLBCL) and Hodgkin’s Lymphoma (N=127 ) in order to minimize heterogeneity. Three year overall survival among DLBCL and HL patients was found to be 0.618 (95% CI 0.490-0.722) and 0.828 (95% CI 0.701-0.904), respectively. Stage IV disease at transplantation, was found to be a statistically significant poor prognostic factor. Higher ECOG performance status and
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progressive disease at transplantation were found to be borderline significant. No IPS cases were reported in our cohort. Six patients died due to treatment related toxicity during the first 100 days. Three-year PFS was found to be 0.5 (95% CI 0.37-0.61) for HL patients and
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0.49 (95% CI 0.36-0.60) for DLBCL patients. Our results are encouraging and justify evaluation of TECAM versus BEAM in a prospective multicenter study in a large homogenous
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patient population.
2
Introduction
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High dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for chemosensitive relapsed non Hodgkin lymphoma (NHL) and Hodgkin lymphoma 1, 2. Initial prospective studies compared chemotherapy plus radiotherapy to radiotherapy plus high dose chemotherapy and ASCT. At five years, the rate of event-free
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survival was 46 percent in the transplantation group and 12 percent in the group receiving chemotherapy without transplantation , and the rate of overall survival was 53 and 32
percent, respectively 3. Friedberg et al reported secondary myelodysplastic syndrome
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(MDS) in 7.4% of patients at 47 months and 19.8% at ten years in 552 patients who
underwent ASCT for NHL, with a uniform ablative regimen of cyclophosphamide and total
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body irradiation (TBI) 4. Due to this serious complication, most transplant centers moved away from TBI containing regimens towards chemotherapy based regimens. Currently, the choice of conditioning regimen varies and is typically based on institutional experience. In most centers, CBV (Cyclophosphamide, Carmustine (BCNU), and Etoposide ) or BEAM
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(carmustine, etoposide, cytarabine, and melphalan ) regimens are the conditioning regimens of choice for patients undergoing ASCT. High dose BCNU and TBI based conditioning regimens with ASCT have been associated with Idiopathic Pneumonitis syndrome (IPS),
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causing significant morbidity and mortality. The occurrence of IPS after CBV or TBI based regimens was reported in 6% and 5% of patients, respectively. The incidence of IPS, one
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year after ASCT with BEAM as the conditioning regimen was reported to be around 3% 5 . Relapsed or refractory non Hodgkin lymphoma (NHL) patients conditioned with BEAM were reported to achieve a complete remission at one month of 62.8%, with a median EFS and OS of 16.1 and 30.6 months, respectively 6. Relapsed or refractory Hodgkin lymphoma (HL) patients conditioned with BEAM were reported to achieve a median EFS and OS of 12 and 53 months, respectively 7. This high incidence of IPS, related mainly to the use of BCNU, and the relatively short EFS and OS has led many centers to create modified regimens, replacing
3
carmustine with other agents as a strategy to both increase efficacy and reduce toxicities
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associated with the BEAM regimen. Due to its relative safety and a low-toxicity profile, thiotepa has been used in the context of stem cell transplantation for multiple myeloma, breast carcinoma, leukemia and lymphoma. In a leukemia animal model, it was shown that thiotepa has a synergistic or additive effect
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when combined with other agents. The activity of high dose cyclophosphamide in lymphoma patients is well established; the combination of thiotepa and
cyclophosphamide was as effective as the commonly used myeloablative combinations 8, 9.
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Recent reports have shown thiotepa based regimens to have similar efficacy and tolerability as the conventional BEAM regimen.10 The aim of our study was to report the long-term
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safety and efficacy of our TECAM conditioning protocol consisting of thiotepa, etoposide, cyclophosphamide, cytarabine and melphalan at Hadassah Medical Center.
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Patients and Methods:
Data for all patients are routinely collected at the bone marrow transplantation (BMT) department using a predefined case report form. Medical records and laboratory data were
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reviewed from time of referral to our center for lymphoma treatment until last follow up. We retrospectively analyzed our cohort of NHL and HL patients who underwent ASCT with
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the TECAM conditioning regimen, at the Hadassah medical center BMT department, between 2000 and 2013. At this time period, TECAM was the standard conditioning protocol used at our center.
Two hundred and twelve patients, 114 males and 98 females, were included. Seventy-four underwent ASCT for HL while 138 for NHL. The median follow up period was 2.84 years (max 13.38 years) from ASCT and 3.52 years for surviving patients. The TECAM conditioning protocol consisted of etoposide 200mg/m2 from day -6 to -3, thiotepa 40mg/m2 from day -5 4
to -2, cytarabine 200mg/m2 from day -4 to -1, cyclophosphamide 60mg/kg on day -3 and
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melphalan 60mg/m2 on day -2 and -1 . Doses were adjusted as follows: For patients between the ages of 40-50, doses were reduced by 0.5% per year. For patients older than 50 years, doses were reduced by 1% per year. For patients with BMI above 35 doses were adjusted for BMI of 35.
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the principles of the Helsinki Declaration (0053-16-HMO).
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The study was performed with institutional review board approval and in accordance with
Peripheral stem cell harvest
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Peripheral blood stem cells (PBSC) were mobilized by subcutaneous filgrastim (Neupogen, 5 µg/kg twice daily for 5 days) and mobilized PBSC were collected on days 5 and 6 (if needed).
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Supportive Care
Prior to transplantation, all patients received high dose trimethoprim/sulfamethoxazole until day −2, acyclovir from the initiation of therapy until day +120 and allopurinol until day −1.
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Trimethoprim/sulfamethoxazole was reinstituted for a period of 6 months after recovery from neutropenia. Febrile neutropenia was treated according to the hospital's infectious
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disease protocols.
Patients were treated in reverse isolation HEPA-filtered rooms, and received a regular diet. Additional supportive measures, such as analgesics, parenteral nutrition and blood component transfusions, were administered as necessary. Patients were treated with post transplant subcutaneous filgrastim 5 µg/kg/d starting from day +6 until stable engraftment of neutrophils.
5
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Assessment of engraftment and toxicity The time of leukocyte engraftment was defined to be the first of three consecutive days with
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an absolute neutrophil count (ANC) 0.5 x 109/L, and that of platelet engraftment was defined as the day that platelet count was > 20 x 109/L with no requirement of platelet transfusion. Veno-occlusive disease (VOD) was classified according to the Baltimore criteria and defined
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as severe when complicated by multiorgan failure11.Treatment-related mortality (TRM) was defined as any death after SCT not caused by relapse or disease progression within 100 days
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of transplantation. Overall survival (OS) was defined as time from the day of transplantation to death from any cause, or last follow-up. Relapse was defined as the recurrence of the hematological malignancy, after the initial achievement of complete remission. Three-year non-relapse mortality (NRM) was defined as any death without recurrent disease. Progression-free survival (PFS) was defined as the time from high dose chemotherapy with
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ASCT to either relapse or death which ever occurred first or at last contact. Due to the heterogeneity of the lymphoma subtypes, OS and PFS analysis were performed solely in the
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DLBCL and HL patient groups.
Definitions and statistical considerations The pre and post-transplant lymphoma status were classified according to the following criteria: Complete response (CR, absence of all clinical and radiographic evidence of disease), partial response (PR,> 50% reduction of the surface area of all measurable disease), stable disease (SD, <50% reduction of the surface area of all measurable disease) and progressive disease (PD, any progression of disease). 6
ACCEPTED MANUSCRIPT Descriptive statistics including counts and percentage for categorical variables, and mean, standard deviation (SD), median and range, and 95% confidence limits of the mean as appropriate were used for describing patients' characteristics.
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test was applied for comparing survival curves, using SAS 9.2.
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The Kaplan-Meier survival model was used for assessing survival curves, and the log-rank
7
Results:
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Patients' characteristics Two hundred and twenty seven patients underwent ASCT with the TECAM conditioning protocol between the years 2000 to 2013. Fifteen patients were not included in the analysis
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due to lack of complete data. Two hundred and twelve patients were included in our cohort. Median age was 46.3 years (range: 16-71). Patients' characteristics prior to ASCT are summarized in table 1. One hundred and twenty seven patients received high dose
chemotherapy and ASCT for Hodgkin and diffuse large B cell lymphomas. Other lymphoma
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subtypes included: T cell, low grade transformed, follicular and mantle. The median number
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of treatment lines before ASCT was 2 (range: 1-7). One hundred and eighty patients (85%) were transplanted with responsive disease, of them 101 were in CR. The vast majority of patients in the HL and DLBCL groups were transplanted due to primary refractory or
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relapsed disease.
Hematopoietic engraftment and toxicity
Hematopoietic engraftment and toxicity details are summarized in table 2. The median time
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to recovery of absolute neutrophil count>0.5x109/L was 12 days and platelet count>20x109/L was 17 days. Three patients died before day +30 due to sepsis with no engraftment. One
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patient died from persistent disease with bone marrow involvement and no engraftment. Two patients failed to achieve platelet engraftment. Fifty percent of patients suffered from mucositis, 52% needed TPN support, 30% had an episode of bacteremia, 4.7% septic shock and 16% renal failure(defined as creatinine elevation >x1.5 from baseline) at any time point during hospitalization for transplantation. No patient developed severe VOD. Thiotepa related skin toxicity was not observed. The median number of hospitalization days was 26 (range 18-124). Eight patients (3.77%) died during the first 100 days. Causes of death were: 8
active disease in two patients, infection in four patients and multiorgan failure in two
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patients.
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Outcome and survival analysis To minimize heterogeneity of lymphoma subtypes, survival analysis were done on the two
largest lymphoma subgroups comprising the majority of patients: HL (74 patients) and DLBCL
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(73 patients). The overall survival of patient with DLBCL and HL is shown in Fig. 1. Three
years overall survival among DLBCL and HL patients was found to be 0.618 (95% CI 0.490-
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0.722) and 0.828 (95% CI 0.701-0.904), respectively (p = 0.0058). Pre-transplantation stage IV disease, was found to be a statistically significant bad prognostic factor (p=0.0002). Higher ECOG performance status and progressive disease at transplantation were found to be borderline significant (p=0.07). Age, dose reduction of conditioning protocol and number of
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treatment lines before ASCT, had no influence on survival (table 3). In contrast to the worse OS of patients in stage 4 disease at transplantation, we found no impact of disease stage on OS of patients in stages I to III. Three months post ASCT, 61.9% of patients were in CR, 4.1%
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in PR and 19.72% were found to be with progressive disease, 4.76% died during the first three months post ASCT and for 9.52% data was not available. In the HL group 66.2% were in
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CR and 8.1% were in PR, while in the DLBCL group 57.5% were in CR and 8.21% were in PR. Fifteen patients underwent planned consolidation with radiotherapy post ASCT and 26 patients received immunotherapy. Three-year PFS of 127 patients with DLBCL and HL is shown in Fig. 2. Three-year PFS was found to be 0.5 (95% CI 0.37-0.61) for HL patients and 0.49 (95% CI 0.36-0.60) for DLBCL patients. Three-year PFS for patients achieving CR after transplantation was significantly
9
better (0.660- 95% CI 0.546-0.752) than for those who were in PR (0.33 - 95% CI 0.046-
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0.675) or in PD (0.00) with a P value of <0.0001 (table 4). Of the 127 patients with DLBCL and HD, 19 underwent allogeneic HSCT, of them five survived with a median follow up of 6 years.
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In the group of 212 transplanted lymphoma patients, with a maximal observation time of 13.38 years from ASCT, a second malignancy was diagnosed in 9 patients (4.24%): five had MDS or acute myeloid leukemia (AML), one developed peripheral T cell lymphoma and melanoma in situ, one renal cell carcinoma, one breast carcinoma and one epidermoid
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carcinoma of the parotid. Other reported late complications were: one patient developed
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avascular necrosis of the hip, and four patients suffered from recurrent infections (of these two had hypogammaglobulinemia). One patient experienced hepatitis B reactivation. No patient was reported to suffer from IPS.
Out of the 212 transplanted patients, 76 (35.8%) patients died during the observation period, of them in 61(80.26%) the cause of death was relapsed lymphoma. Six patients died
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due to transplant related toxicity, of them four died due to infection and two due to multiorgan failure. Six patients died from secondary malignancy (5 with MDS/AML and 1 from T
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cell lymphoma), one patient died from unrelated causes and two patients from unknown
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causes. The incidence of 3 year NRM was 2.8%.
10
Discussion:
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High dose chemotherapy and autologous stem cell transplantation (ASCT) is the current standard of care for chemo sensitive relapsed non Hodgkin lymphoma (NHL) and Hodgkin lymphoma. Currently, the choice of conditioning regimen varies and is typically based on institutional experience. In most centers, CBV or BEAM regimens are the conditioning
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regimens of choice for patients undergoing ASCT 6, 7, 12, 13. Due to concern of late toxicities, supply and cost issues for carmustine, carmustine is not an option in many centers. Alternative regimens such as etoposide and melphalan (VP16/MEL); gemcitabine,
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busulphan, and melphalan (GemBuMel); and busulfan, cyclophosphamide, etoposide
(BuCyE) are used at many institutions 14. Wang et al compared retrospectively 52 patients
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receiving CBV to 20 patients receiving BEAM as conditioning regimen in ASCT for NHL and HL. They showed a better OS (with a mean follow-up of 16 months) for patients receiving BEAM as compared to CBV (84 vs. 60% )13. Chen et al retrospectively studied 4917 patients who underwent ASCT comparing BEAM, CBV, BuCY and TBI containing regimens. For NHL
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patients, probability of three year OS were 64% for BEAM, 60% and 52% for CBV –BCNU low or high respectively, 49% for BuCy and 50% for TBI. For HL patients the probability of three year OS using the same conditioning regimens were 79%, 73%, 68%, 65% and 47%
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respectively5. Our results using the TECAM conditioning protocol are comparable to those reported for BEAM and CBV, showing the probability of overall survival among DLBCL and HL
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patients to be 0.618(95% CI 0.573-0.738) and 0.828(95% CI 0.701-0.904), respectively. Using TECAM as our conditioning regimen, we observed TRM and 3 year NRM in only 6 patients out of a cohort of 212 patients (2.83%). Chen et al reported a 1 year TRM incidence of 4% in the BEAM group and 7 and 8% in the CBV-BCNU low and high groups respectively 5. Puig et al compared TRM in 113 patients with NHL and HL undergoing ASCT. They reported a cumulative incidences of TRM of 25% in the CBV and 7% in the BEAM group 15. E Joffe et al 16
11
recently reported a TRM of 1.6% using TECAM for 65 lymphoma patients. Our TRM results
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are comparable to those reported by others using BEAM or CBV or conditioning protocols. Our retrospective study shows a rate of 50% mucositis (of them 27.1% grade IV) and 52% of patients receiving TPN support. Our department policy in TPN support is not only related to high grade mucositis but also for patients with low intake due to other reasons (e.g. nausea,
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vomiting ect.). Although we report a high rate of TPN support, our mucositis rate is similar to the rate reported in other conditioning regimens. The EBMT lymphoma working party
reported in a retrospective study comparing BEAM to thiotepa based TEAM regimens, a
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mucositis rate of 60% in both groups correlating with many other similar reports10, 12, 13.
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High dose BCNU and TBI based regimens have been associated with Idiopathic Pneumonitis syndrome after ASCT, causing significant morbidity and mortality. Lane at al reported an incidence of IPS of 22% in 222 patients treated with high dose BCNU as part of CBV protocol at the Dana Farber Cancer Institute, with a median time to development of IPS being 50 days 17
. Chen et al reported an incidence of IPS by 1 year after ASCT to be 3% with BEAM and CBV
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(low) 4% for BuCy and 5% for TBI. In these patients, those who developed IPS had a significantly higher rate of TRM and shorter PFS and OS 5. In our cohort, none of the patients conditioned for ASCT with the TECAM protocol, suffered from clinical symptoms or
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laboratory proven IPS. Secondary malignancies have been reported to be the most common non relapse related cause of death in 9 out of 150 (6%) Hodgkins' patients treated with HDT-
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ASCT in the Norway national cohort 2. Goodman et al at the Memorial Sloan-Kettering Cancer Center reported second malignancies in 15 patients out of 153 Hodgkin patients who survived for more than 2 years after ASCT 18. Lenz et al in Germany reported an estimated 5year risk for secondary hematologic malignancy of 3.8%, in patients undergoing ASCT conditioned with TBI and cyclophosphamide for low grade lymphoma.19. The Nebraska Lymphoma Study Group (NLSG) reported on 2 year survivors after ASCT for Hodgkin lymphoma patients: they reported deaths from secondary malignancies in 10% of patients 12
receiving CBV and 5% in the BEAM group. We have reported a second malignancy in 9
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patients out of 212 (4.24%), of which 5(2.35%) had a secondary hematologic malignancy 20. Like others have shown, we report worse OS for patients with progressive disease or stage 4 disease at transplantation, emphasizing the importance of a chemo sensitive disease before ASCT. Interestingly, in our cohort, there was no difference in OS between stages 0 to III. This
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finding raises the question of the necessity to aim for CR before transplantation, with the cost of more chemotherapeutic lines. Larger cohorts are needed to address this question.
A retrospective comparison between TECAM and BEAM as conditioning regimens for high
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risk lymphoma patients was recently published. One hundred and twenty five patients were analyzed. Of them 65 received the TECAM protocol. The reported results are comparable to
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ours, even though the patients' cohort is significantly smaller and heterogeneous in terms of lymphoma subtypes. Like us, they conclude that TECAM has comparable efficacy and safety profile as BEAM and suggest an advantage using TECAM for older patients16. Our study limitations are those inherent in its retrospective design and the different
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proportions of patients with different lymphoma subtypes. In addition, we have reported our experience using TECAM for 13 years (between the years 2000 and 2013), a time span in which many new agents were added to the treatment of patients including mabthera,
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care21-24.
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brentuximab, new antibiotics and antifungal agents and development of a better supportive
With the limitations of a retrospective analysis we conclude that our TECAM
conditioning regimen shows similar efficacy to the commonly used BEAM protocol. The toxicity profile of TECAM was found to be similar to the BCNU containing regimens, excluding pulmonary fibrosis - a complication that is known to have a profoundly negative effect on overall survival and is related to high dose BCNU. Our results encourage considering TECAM as an alternative conditioning regimen for ASCT in high risk lymphoma
13
patients. A Large prospective homogenous clinical trial designed to verify our results is
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warranted.
References:
Moskowitz AJ, Moskowitz CH. Controversies in the treatment of lymphoma with autologous transplantation. Oncologist 2009; 14(9): 921-929. e-pub ahead of print 2009/09/10; doi: theoncologist.2009-0162 [pii] 10.1634/theoncologist.2009-0162
2.
Smeland KB, Kiserud CE, Lauritzsen GF, Fagerli UM, Falk RS, Fluge O et al. Conditional survival and excess mortality after high-dose therapy with autologous stem cell transplantation for adult refractory or relapsed Hodgkin lymphoma in Norway. Haematologica; 100(6): e240-243. e-pub ahead of print 2015/02/16; doi: haematol.2014.119214 [pii]10.3324/haematol.2014.119214
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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 chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995; 333(23): 1540-1545. e-pub ahead of print 1995/12/07; doi: 10.1056/NEJM199512073332305
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Friedberg JW, Neuberg D, Stone RM, Alyea E, Jallow H, LaCasce A et al. Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 1999; 17(10): 3128-3135. e-pub ahead of print 1999/10/03;
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Chen YB, Lane AA, Logan BR, Zhu X, Akpek G, Aljurf MD et al. Impact of conditioning regimen on outcomes for patients with lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant; 21(6): 1046-1053. e-pub ahead of print 2015/02/18; doi: S1083-8791(15)00112-3 [pii] 10.1016/j.bbmt.2015.02.005
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Kim JE, Lee DH, Yoo C, Kim S, Kim SW, Lee JS et al. BEAM or BuCyE high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients: a single center comparative analysis of efficacy and toxicity. Leuk Res; 35(2): 183-187. e-pub ahead of print 2010/08/06; doi: S01452126(10)00359-0 [pii] 10.1016/j.leukres.2010.07.016
Nieto Y, Popat U, Anderlini P, Valdez B, Andersson B, Liu P et al. Autologous stem cell transplantation for refractory or poor-risk relapsed Hodgkin's lymphoma: effect of 14
the specific high-dose chemotherapy regimen on outcome. Biol Blood Marrow ACCEPTED MANUSCRIPT Transplant; 19(3): 410-417. e-pub ahead of print 2012/11/07; doi: S10838791(12)00459-4 [pii] 10.1016/j.bbmt.2012.10.029 Abdul-Hai A, Weiss L, Ergas D, Resnick IB, Slavin S, Shapira MY. The effect of highdose thiotepa, alone or in combination with other chemotherapeutic agents, on a murine B-cell leukemia model simulating autologous stem cell transplantation. Bone Marrow Transplant 2007; 40(9): 891-896. e-pub ahead of print 2007/09/05; doi: 1705838 [pii] 10.1038/sj.bmt.1705838
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Abu Zaid B, Abdul-Hai A, Grotto I, Dray L, Resnick IB, Tsirigotis PD et al. Autologous transplant in multiple myeloma with an augmented conditioning protocol. Leuk Lymphoma; 54(11): 2480-2484. e-pub ahead of print 2013/03/09; doi: 10.3109/10428194.2013.782608
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Sellner L, Boumendil A, Finel H, Choquet S, de Rosa G, Falzetti F et al. Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT. Bone Marrow Transplant 2016; 51(2): 212-218. doi: 10.1038/bmt.2015.273
11.
Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A et al. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol; 163(4): 444-457. e-pub ahead of print 2013/10/10; doi: 10.1111/bjh.12558
12.
Falzetti F, Di Ianni M, Ballanti S, Iodice G, Reale A, Minelli O et al. High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk non-Hodgkin lymphoma. Clin Exp Med; 12(3): 165-171. e-pub ahead of print 2011/09/20; doi: 10.1007/s10238-011-0157-2
13.
Wang EH, Chen YA, Corringham S, Bashey A, Holman P, Ball ED et al. High-dose CEB vs BEAM with autologous stem cell transplant in lymphoma. Bone Marrow Transplant 2004; 34(7): 581-587. e-pub ahead of print 2004/07/27; doi: 10.1038/sj.bmt.1704637 1704637 [pii]
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Isidori A, Christofides A, Visani G. Novel regimens prior to autologous stem cell transplantation for the management of adults with relapsed/refractory non-Hodgkin lymphoma and Hodgkin lymphoma: alternatives to BEAM conditioning. Leuk Lymphoma 2016; 57(11): 2499-2509. doi: 10.1080/10428194.2016.1185785
15.
Puig N, de la Rubia J, Remigia MJ, Jarque I, Martin G, Cupelli L et al. Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation. Leuk Lymphoma 2006; 47(8): 1488-1494. e-pub ahead of print 2006/09/13; doi: X7L0307307456J73 [pii] 10.1080/10428190500527769
15
Joffe E, Rosenberg D ACCEPTED , Rozovski U, Perry C, Kirgner I, Trestman S, Gur O, Aviv F, MANUSCRIPT Sarid N, Kolomansky A, Gepstein L, Herishanu Y, Naparstek E. Replacing carmustine by thiotepa and cyclophosphamide for autologous stem cell transplantation in Hodgkin's and non-Hodgkin's B-cell lymphoma. Bone Marrow Transplant 2017; Oct 16. doi: 10.1038/bmt.2017.205. [Epub ahead of print].
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Lane AA, Armand P, Feng Y, Neuberg DS, Abramson JS, Brown JR et al. Risk factors for development of pneumonitis after high-dose chemotherapy with cyclophosphamide, BCNU and etoposide followed by autologous stem cell transplant. Leuk Lymphoma; 53(6): 1130-1136. e-pub ahead of print 2011/12/03; doi: 10.3109/10428194.2011.645208
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Goodman KA, Riedel E, Serrano V, Gulati S, Moskowitz CH, Yahalom J. Long-term effects of high-dose chemotherapy and radiation for relapsed and refractory Hodgkin's lymphoma. J Clin Oncol 2008; 26(32): 5240-5247. e-pub ahead of print 2008/09/24; doi: JCO.2007.15.5507 [pii] 10.1200/JCO.2007.15.5507
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Lenz G, Dreyling M, Schiegnitz E, Haferlach T, Hasford J, Unterhalt M et al. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 2004; 22(24): 4926-4933. e-pub ahead of print 2004/12/22; doi: 22/24/4926 [pii] 10.1200/JCO.2004.06.016
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William BM, Loberiza FR, Jr., Whalen V, Bierman PJ, Bociek RG, Vose JM et al. Impact of conditioning regimen on outcome of 2-year disease-free survivors of autologous stem cell transplantation for Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk; 13(4): 417-423. e-pub ahead of print 2013/06/19; doi: S2152-2650(13)00109-2 [pii] 10.1016/j.clml.2013.03.009
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Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H et al. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol; 168(6): 824-834. e-pub ahead of print 2014/12/30; doi: 10.1111/bjh.13234
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Pham A, Chen R. Brentuximab vedotin for the treatment of Hodgkin's lymphoma. Expert Rev Hematol; 8(4): 403-412. e-pub ahead of print 2015/05/15; doi: 10.1586/17474086.2015.1044432
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Isidori A, Clissa C, Loscocco F, Guiducci B, Barulli S, Malerba L et al. Advancement in high dose therapy and autologous stem cell rescue in lymphoma. World J Stem Cells; 7(7): 1039-1046. e-pub ahead of print 2015/09/04; doi: 10.4252/wjsc.v7.i7.1039
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Fernandez HF, Escalon MP, Pereira D, Lazarus HM. Autotransplant conditioning regimens for aggressive lymphoma: are we on the right road? Bone Marrow 16
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Transplant 2007; 40(6): 505-513. e-pub ahead of print 2007/06/26; doi: 1705744 ACCEPTED MANUSCRIPT [pii] 10.1038/sj.bmt.1705744
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Table 1. Patients' characteristics prior to ASCT.
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Variable
N=212
Age(years)
114 (46%)
Male
98 (54%)
Female Type of lymphoma
53 (25%)
Hodgkin's
74 (34.9%)
T cell
23 (10.8%)
Low grade transformed to DLBCL
20 (9.4%) 15 (7.1%)
Mantle
14 (6.6%)
Follicular
13 (6.1%)
Other NHL ECOG performance status at ASCT
160 (75.5%)
0
34 (16%)
1
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4 (1.9%)
2
14 (6.6%)
Unknown Disease status at ASCT Complete Response
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Partial Response Stable Disease
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Diffuse large B cell
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Progressive Disease Unknown
101 (47.6%) 79 (37.3%) 4 (1.9%) 26 (12.3%) 2 (0.9%)
No. of treatment lines before ASCT Median (range)
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Gender
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46.3 (16-71)
Median (range)
2.0 (1-7)
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ACCEPTED MANUSCRIPT Table 2. Hematopoietic engraftment and toxicity.
absolute neutrophil count>500/mm3 (days) Median (Range) platelets count>20,000 (days)
12 (9-72)
Median (Range) No. of Hospitalization days Median (Range) Mucositis (No. of Patients,%) Grade I Grade II Grade III Grade IV Unknown No. of TPN days Median (Range) Infectious complications (No. of patients) Bacteremia Septic Shock Transplant related mortality No. of patients
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26 (18-124) 106 (50%) 24 (22.6%) 17 (16%) 21 (19.8%) 29 (27.3%) 15 (14.1%)
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17 (8-935)
2 (0-49)
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64 (30%) 10 (4.7%)
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6 (2.83%)
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SC
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survival.
20
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Event N (%)
3 years overall survival
95% CI
P value
DLBCL
73
26(35.62)
0.618
0.49-0.72
0.0013
HL
74
10(13.51)
0.829
0.70-0.90
0
69
16(23.2)
0.751
0.62-0.84
I
16
5(31.2)
0.628
0.32-0.83
II
36
3(8.3)
0.901
0.72-0.97
III
10
3(30.00)
0.700
IV
14
8(57.14)
0.283
UN
2
ECOG at entry to ASCT 110
22(20.0)
1
22
8(36.3)
2
3
2(66.7)
12
UN
0.63
0.39-0.73
0.33
0.00-0.66
4(33.3)
0.66
0.33-0.86
16(23.2)
0.75
0.62-0.84
11(18.97)
0.71
0.62-0.86
3
1(33.33)
0.50
0.006-0.91
17
8(47.06)
0.48
0.21-0.70
69
PR
58
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CR
PD
SC 0.67-0.82
Disease status at entry to ASCT
SD
0.06-0.55
0.75
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0
0.0002
0.33-0.89
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Stage at entry to ASCT
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Disease
0.0760
0.0721
3 month post ASCT disease status CR
91
7(7.69)
0.90
0.80-0.95
PR
6
1(16.67)
0.83
0.27-0.97
PD
29
19(65.5)
0.22
0.08-0.41
UN
14
0.73
0.38-0.91
3(21.43)
21
<0.0001
Table 4. Univariate analysis of three-year Progression Free Survival (PFS).
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N=147
EVENT N (%)
3 YEAR PFS
95% CI
P VALUE
DLBCL
73
35 (47.95)
0.49
0.37-0.60
0.386
HL
74
33 (44.59)
0.50
0.37-0.61
0
110
48 (43.64)
0.50
0.40-0.60
1
22
11 (50.00)
0.50
0.28-0.68
2
3
2 (66.67)
0.33
0.00-0.77
12
7 (58.33)
0.42
0.15-0.66
0.45-0.69
Disease
ECOG at entry to ASCT
Disease status at entry to ASCT
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UN
69
27 (39.13)
0.58
PR
58
30 (51.72)
0.44
SD
3
1 (33.33)
0.50
PD
17
10 (58.82)
0.34
CR
91
28 (30.77)
0.66
0.57-0.74
PR
6
4 (66.67)
0.33
0.08-0.63
PD
29
27(93.10)
0.00
0.000
UN
14
3 (21.43)
0.75
0.41-0.91
17 (34.69)
0.62
0.46-0.74
4 (66.67)
0.33
0.04-0.67
11 (91.67)
0.00
0(0.00)
0.642
0.71
0.54-0.82
49
PR
6
PD
12
UN
6
0.30-0.56
0.006-0.91 0.11-0.58
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3 month disease status DLBCL
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CR
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3 Month disease status HL
CR
42
11 (26.19)
PR
7
0 (0.00)
PD
17
16(94.12)
0.05
0.00-0.23
UN
8
3(38.46)
0.62
0.23-0.86
22
0.2226
SC
CR
3 month post ASCT disease status
0.4722
<0.0001
<0.0001
<0.0001
Figures Legends:
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Fig.1: Ten-year overall survival curves by disease group.
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Fig.2 Ten-year event free survival curves by disease group.
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ACCEPTED MANUSCRIPT Fig.1: Ten year overall survival curves by disease group.
Overall Survival (Kaplan Meier)
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0.8
0.6
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Survival Distribution Function Estimate
1.0
0
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0.4
6
4
2
time (years)
DX Log-rank p-value=0.0029
HD
DLBCL+Transformed
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HD: Hodgkin's disease; DLBCL: diffuse large B cell lymphoma
8
10
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Fig.2 Ten year event free survival curves by disease group. Event free survival free (kaplan Meier) Progression Survival (Kaplan Meier)
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1.0
SC
0.6
0.4
0.2 0
2
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Survival Distribution Function Estimate
0.8
4
6
8
time (years)
DX
HD -----------DLBCL+Transformed HD DLBCL
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Log-rank p-value=0.1843
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EFS: event free Survival; HD: Hodgkin's disease; DLBCL: diffuse large B cell lymphoma
10
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