|Year : 2020 | Volume
| Issue : 1 | Page : 13-18
Gemcitabine, dexamethasone, and cisplatin salvage in relapsed lymphomas: A single institutional experience
Avaronnan Manuprasad, Praveen Kumar Shenoy, Vineetha Raghavan, KM Shiljina, Chandran K Nair
Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Kannur, Kerala, India
|Date of Submission||27-Nov-2019|
|Date of Decision||05-Dec-2019|
|Date of Acceptance||14-Dec-2019|
|Date of Web Publication||24-Feb-2020|
Praveen Kumar Shenoy
Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Thalaserry, Kannur - 670 103, Kerala
Source of Support: None, Conflict of Interest: None
Introduction: Salvage chemotherapy followed by autologous stem cell transplantation is the standard of care in relapsed lymphoma. The optimal regimen for salvage is not defined. The combination of gemcitabine, dexamethasone, and cisplatin (GDP) is an outpatient regimen which can lead to high response rates with minimal toxicity.
Methods: This was a retrospective study of all patients with relapsed diffuse large B-cell lymphoma, Hodgkin's lymphoma (HL), or peripheral T-cell lymphoma who received GDP as salvage chemotherapy between January 2014 and December 2017. Baseline characteristics, treatment details, toxicity, and outcomes including survival were analyzed.
Results: We included 39 patients in the study. The most common indication was relapsed high grade B-cell non-Hodgkin's lymphoma (NHL) (n = 20, 51%) followed by HL (n = 10, 25%) and T-cell NHL (n = 9, 24%). The median age was 46 years (range, 17–62 years); 27 patients (69%) were males. The most common Grade 3/4 toxicity was thrombocytopenia (n = 7, 18%) followed by neutropenia (n = 5, 12%) and anemia (n = 3, 8%). Overall response rate for GDP was 64% (complete response-10%, partial response-54%). Of the 30 patients who were eligible for transplant, 16 (57%) could undergo transplant. At a median follow-up of 12 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 50% and 38% for the entire patient cohort. The 2-year OS was 68% in the patients who underwent transplant and 38% in the non-transplant group. The 2-year PFS was 58% in those who underwent transplant and 18% in those who did not undergo transplant.
Conclusions: GDP is an effective and well-tolerated salvage regimen in relapsed lymphoma. The regimen is feasible in a resource-limited setting.
Keywords: Diffuse large B-cell lymphoma, gemcitabine, dexamethasone, cisplatin, India, relapsed lymphoma, salvage chemotherapy, GDP, LMIC, DLBCL, lymphoma
|How to cite this article:|
Manuprasad A, Shenoy PK, Raghavan V, Shiljina K M, Nair CK. Gemcitabine, dexamethasone, and cisplatin salvage in relapsed lymphomas: A single institutional experience. Cancer Res Stat Treat 2020;3:13-8
|How to cite this URL:|
Manuprasad A, Shenoy PK, Raghavan V, Shiljina K M, Nair CK. Gemcitabine, dexamethasone, and cisplatin salvage in relapsed lymphomas: A single institutional experience. Cancer Res Stat Treat [serial online] 2020 [cited 2022 May 20];3:13-8. Available from: https://www.crstonline.com/text.asp?2020/3/1/13/279067
| Introduction|| |
Lymphomas are considered highly curable malignancies. Yet, between 30% and 40% of the patients with diffuse large B-cell lymphoma (DLBCL) and about 20% of the patients with Hodgkin's Lymphoma (HL) develop relapsed/refractory disease., Salvage chemotherapy followed by autologous stem cell transplant is considered the standard treatment in patients with relapsed lymphoma. However, most of the salvage regimens used in patients with lymphoma are highly toxic and require hospitalization which makes the treatment of relapsed lymphoma challenging in a resource-limited setting. In addition, many of the patients may not be fit for curative intent treatment. There are multiple regimens which can be used in this setting and there is no evidence to recommend one over another. Commonly used regimens include dexamethasone, ara-C, and cisplatin (DHAP), ifosfamide, carboplatin, and etoposide (ICE) and gemcitabine-based regimens., Apart from high response rates, there are other important factors to be considered while choosing a salvage regimen including low toxicity, ease of administration, and favorable effect on stem cell mobilization.
Gemcitabine/dexamethasone/cisplatin (GDP) is considered to be an effective but less toxic salvage regimen that can be delivered on an outpatient basis and can be used for relapsed Non-HL (NHL), HL and T-cell lymphomas., Moreover, it can be used as a salvage regimen before autologous transplant as well as definitive salvage when transplant is not feasible. However, there are only limited data regarding the use of gemcitabine-based regimens or any form of salvage in relapsed lymphomas from low middle-income countries (LMIC). Although there are multiple reports from India on the first-line treatment of lymphomas, data from the relapsed setting are scant. Here, we share our experience with the GDP regimen in all relapsed lymphomas including DLBCL, HL, and peripheral T-cell lymphoma (PTCL).
| Methods|| |
This was a retrospective study conducted in the Department of Clinical Hematology and Medical Oncology of a tertiary cancer center located in rural India. The study was approved by the Institutional Review Board (IRB) [Supplementary Appendix 1]. As per the policy of our IRB, written informed consent was not required as this was a retrospective study. The study was not registered in a public clinical trials registry, as it was a retrospective study. No funding was obtained for the study. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki, principles of good clinical practice, and the guidelines established by the Indian Council of Medical Research.
Patients with relapsed or refractory lymphomas (DLBCL, HL, or T-Cell NHL) who received salvage chemotherapy with GDP regimen were included in the study. Refractory disease was defined as disease not responding to treatment or progression within 3 months of the completion of treatment. Patients who received any regimen other than GDP were excluded from the study. Primary objective of the study was to assess the toxicity and outcomes of GDP salvage in patients with relapsed lymphoma. Eligible patients were identified from the day care chemotherapy register. In our center, patients with relapsed lymphomas were taken up for salvage chemotherapy after multidisciplinary tumor board discussion. All patients with good performance status and adequate end-organ function received GDP regimen as the salvage. Patients who were unfit to receive intensive chemotherapy were considered for best supportive care. Case records of all patients who received salvage chemotherapy with GDP during the study period (2014–2017) were reviewed [Figure 1]. GDP regimen included gemcitabine 1000 mg/m2 intravenously (IV) on days 1 and 8, dexamethasone 40 mg orally on days 1–4, and cisplatin 75 mg/m2 IV on day 1; every 21 days. All the patients received supportive medications including aprepitant and ondansetron along with hydration (1000 ml of 0.9% saline) on day 1 and ondansetron on day 8. Patients who received rituximab were also given antihistamines. Growth factors were used as secondary prophylaxis in the form of conventional granulocyte-colony-stimulating factor daily from day 9. Patients with borderline renal function (creatinine clearance 45–60 ml/min as per Cockcroft–Gault equation) received cisplatin as split doses on days 1 and 8 (37.5 mg/m2 each day) as per British Columbia (BC) Cancer agency protocol for GDP. Those who received cisplatin on day 8 received aprepitant and hydration on day 8 as well. Patients with DLBCL received rituximab at a dose of 375 mg/m2 on day 1. Patients were monitored for toxicity and response before each cycle. Toxicity monitoring included complete blood counts, renal function, liver function, random blood sugar and serum electrolytes on day 1 and complete blood count and renal function test on day 8. Treatment cycles were delayed till absolute neutrophil count was ≥1000 cells/mm3 and platelet counts ≥100,000 cells/mm3 prior to day 1 chemotherapy. Dose reduction was performed in case of the Common Toxicity Criteria for Solid Tumors Grade 3/4 toxicities; dose delays were based on the treating physician's discretion. All the patients underwent interim response assessment at the end of two cycles in the form of computed tomography scan or positron emission tomography scan and bone marrow studies, as indicated. Patients who were eligible for transplant (age below 60 years with no significant comorbidities) and had partial response (PR) or complete response (CR) to chemotherapy as per the response evaluation criteria in solid tumors were taken up for transplant with BEAM (carmustine/etoposide/cytarabine/melphalan) conditioning. Transplant-ineligible patients who had response in the interim scans were continued on GDP chemotherapy for a total of 6 cycles or until they developed dose-limiting toxicity.
|Figure 1: Gemcitabine/dexamethasone/cisplatin salvage in patients with relapsed lymphoma-a single institutional experience-study schema|
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Data including baseline characteristics, toxicity, and outcomes were collected. Statistical analysis was performed using SPSS Version 20 (Armonk, NY, USA: IBM Corp.). Survival was calculated using Kaplan–Meier method. Progression-free survival (PFS) was defined as the duration from the date of diagnosis of relapse to the date of progression. Overall survival (OS) was defined as the duration from the date of the diagnosis of relapse to the date of death due to any cause. Survival between different groups was compared using the log-rank test; a value of P < 0.05 was considered statistically significant. Patients who did not report on the given dates in the clinic and who could not be contacted over phone were considered as lost to follow-up. All patients were included in the analysis as per the intention to treat principle.
| Results|| |
Baseline characteristics and treatment details
Thirty-nine patients were included in the study. They received a total of 130 cycles of chemotherapy. Median age was 46 years and 69% were males [Table 1]. The most common histology was DLBCL followed by HL and T-cell lymphoma. The median time to relapse was 5 months (range, 0–102 months) and eleven patients (28%) had refractory disease. All patients with B-cell lymphomas received rituximab-based chemotherapy as first-line treatment. Gemcitabine-based salvage was given as second line in most of the patients (n = 35, 90%). Two patients (5%) received GDP in the third line and another two patients (5%) in the fourth line. Median number of GDP cycles was 3 (range, 1–6). All the patients with B-cell lymphomas received rituximab along with GDP. Split doses of cisplatin were used in 14 patients (36%).
Our patients tolerated the GDP regimen relatively well. Eleven patients (28%) developed Grade 3/4 toxicity. The most common Grade 3/4 toxicity was thrombocytopenia (n = 7, 18%). Grade 3/4 neutropenia was seen in five patients (12%) and Grade 2 neutropenia was recorded in three patients (8%) Febrile neutropenia was seen in five patients (12%). Other common toxicities (Grade 3/4) are listed in [Table 2]. One patient developed cisplatin-related thrombosis in the form of cerebral venous thrombosis and was managed with conservative measures including anticoagulation. One patient developed hearing loss which was confirmed with pure tone audiometry. Infectious complications were seen in 10 patients (25%) and nine patients (23%) required hospitalization for the management of toxicity. Three patients who had Grade 3/4 toxicity and delay in restarting chemotherapy received dose reductions for the remaining cycles (8%). None of the patients died due to toxicity.
The overall response rate (ORR) to GDP was 64% for the entire group. Four patients had CR (10%), 21 patients (54%) had PR and two patients (5%) had stable disease. Progressive disease was seen in 12 patients (31%). Of the 31 patients who were eligible for transplant, 16 (52%) could undergo transplant. Ten patients did not have chemotherapy-responsive disease, hence were not taken up for transplant. One patient with DLBCL developed progressive disease during the work-up for transplant. Three other patients were not willing for transplant due to financial reasons and fear of complications. Only one patient, who received bendamustine/rituximab in the first-line treatment had inadequate stem cell collection. The median CD34 count was 4.9 × 106/mm3 (range, 1–12); plerixafor was used in three patients.
At a median follow-up of 12 months, the 2-year OS and PFS were 50% and 38% for the entire group. The 2-year OS was higher in patients who underwent transplant compared to those who did not (68% vs. 38%) but was not statistically significant (P = 0.096). Two-year PFS also showed a similar trend (58% vs. 18%) without statistical significance (P = 0.07).
In the 10 patients with HL, the ORR was 90%. Two patients achieved a CR (20%) and 7 achieved a PR (70%). Of the eight patients eligible for transplant, 7 could undergo the procedure. They had a 2-year OS of 64% and 2-year PFS of 55% [Figure 1] and [Figure 2].
|Figure 2: Kaplan–Meier estimates of overall survival for patients with relapsed diffuse large B-cell lymphoma, Hodgkin's lymphoma and T-cell lymphomas who received gemcitabine/dexamethasone/cisplatin regime as salvage|
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Our study included 29 patients with NHL. The ORR was 70% with 10% CR and 60% PR in the 20 patients with DLBCL. Only two of the nine patients with T-cell lymphoma could achieve a PR. Among the patients with NHL, those with T-cell NHL had a 2-year OS of 11%, whereas it was 69% in those with DLBCL. Patients with DLBCL had a higher 2-year PFS compared to those with T-cell NHL (34% vs. 11%) [Figure 2] and [Figure 3].
|Figure 3: Kaplan–Meier estimates of Progression free survival for patients with relapsed diffuse large B-cell lymphoma, Hodgkin's lymphoma, and T-cell lymphomas who received gemcitabine/dexamethasone/cisplatin regime as salvage|
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| Discussion|| |
Our study showed that GDP regimen was a well-tolerated salvage regimen in our patients with relapsed lymphomas producing favorable outcomes, especially in those with DLBCL and HL. The regimen showed response rates comparable to other studies and a favorable effect on the stem cell mobilization. Two-third of our transplant eligible patients had response to treatment though some of them opted against transplant due to social reasons. Patients who underwent transplant had numerically higher survival rates, but some of the patients could be salvaged even without transplant. In addition, GDP had a good tolerability in our patients without any treatment-related mortality. The use of cisplatin in split doses (on day 1 and day 8) enabled us to deliver chemotherapy even in those with borderline renal function. Our study is the first report of GDP in the Indian patients and showed that it is a suitable salvage regimen in our patients. The most common indication in our setting was relapsed B-cell lymphoma followed by Hodgkin's and PTCL. The large retrospective series from the University of British Columbia which reported the outcomes of GDP salvage included 152 patients with DLBCL and 83 patients with HL. Most of our patients received GDP as first-line salvage similar to other studies. Although majority of our patients received GDP with a plan to proceed to transplant, about 23% received GDP with palliative intent.
We found that GDP was a well-tolerated regimen. Although about one-fourth of our patients required hospitalization for the management of toxicity, none of our patients died due to toxicity. Moccia et al. reported a hospitalization rate of 20% in patients with DLBCL and 7% for those with HL. However among Grade 3/4 toxicities, thrombocytopenia was more common than neutropenia unlike other studies. Furthermore, the incidence of Grade 3/4 hematological toxicities was less compared to the initial Phase II trial by Crump et al. who reported granulocytopenia of 64% and thrombocytopenia of 27% against 12% and 18%. Our results were also comparable to those from the study from an Asian country using GDP as salvage regimen in patients with relapsed PTCL.
Regarding the outcomes, our patients with DLBCL and HL had numerically better ORRs compared to other studies. Moccia et al. reported an ORR of 51% for DLBCL and 70% for HL, whereas our patients had ORR of 70% and 90%, respectively. This may be because our study included relatively fewer patients with refractory disease. Another study from India using an alternative gemcitabine-based regimen as a second-line salvage in relapsed HL showed response rates of about 50%. Response in our patients with T-cell lymphomas was extremely poor compared to other studies which have reported response rates around 70% in patients with T-cell lymphomas. Among transplant eligible patients, over 50% could undergo transplant which is similar to what has been reported in other studies. The major reason for not proceeding with transplant was the lack of response to chemotherapy, but about 10% of patients were not willing to undergo the procedure due to financial constraints and fear of complications. This represents a unique problems faced by clinicians in LMICs like India while managing a patient with relapsed lymphoma.,
The 2-year OS and PFS of our patients with HL were comparable to those reported in the study from British Columbia (64% and 55% vs. 85% and 55%). In our patients with DLBCL, the 2-year OS and PFS were 69% and 34%, whereas they were 28% and 21% in the other study. However, our patients with PTCL had an extremely poor survival of 11% at the end of 2 years. This was much lower compared to other reports., It has to be borne in mind that only two patients with T-cell lymphoma could undergo transplant in our series contributing to poor survival. In the entire cohort, patients who underwent transplant had a higher survival compared to those who did not undergo transplant. The lack of statistical significance may be due to the small numbers. Those in the non-transplant group also had a 2-year OS of 34% showing that GDP can produce long-term remissions even without consolidation with transplant. A study from Egypt, in which GDP and DHAP were used as definitive salvage showed similar survival outcomes.
Our results are comparable to other salvage regimens including alternative gemcitabine-based regimens., The DHAP regimen, which is a cisplatin-based, inpatient regime can produce ORR of 69% in relapsed/refractory lymphoma. In case of DLBCL, the ORR for R-GDP was 62.8% and 63.5% for R-ICE similar to our report. Gemcitabine-based regimens studied in relapsed HL also produced response rates ranging between 70% and 80%., The Indian study on outpatient-based regimen (gemcitabine/vinorelbine/dexamethasone) showed an ORR of 64%. ORR in patients on first-line salvage was 71%. Among patients who underwent stem cell collection, 86% had adequate collection (≥2 million cells/kg).
Our study shows that GDP can be considered as one of the optimal salvage regimens in relapsed DLBCL and HL. Lesser toxicity, ease of administration, and favorable effect on stem cell mobilization are advantages for this regimen. However, larger studies with the inclusion of different subgroups and longer follow-up may be needed to confirm this observation. In addition, in a country like ours, cost-effectiveness also should be carefully studied. Our study is limited by its retrospective design, small number of patients, and short follow-up, but it is one of the few reports showing feasibility of gemcitabine-based salvage in a developing country.,
| Conclusions|| |
GDP is an effective, less toxic, outpatient salvage regimen for relapsed lymphoma feasible in resource-limited countries like India. Although favorable outcomes are achieved mainly in patients who undergo autologous stem cell transplantation, it may improve survival in a minority of patients, even without transplant.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Appendix|| |
Supplementary Appendix 1: Study Protocol
GDP as salvage chemotherapy for relapsed lymphomas: Retrospective audit from a tertiary cancer center
PI: Chandran K Nair, Co PI: Dr. Vineetha Raghavan, Dr. Manuprasad, Dr. Praveen Kumar Shenoy
| Introduction|| |
Ideal salvage chemotherapy for relapsed/refractory lymphomas is not well established. The various regimens followed are DHAP, ICE, GDP, etc. Among this, the only regimen which can be safely administered as outpatient setting is GDP. In a phase III trial, GDP has been found to be noninferior to DHAP with less toxicity. Other than this, there is no head-to-head comparison between these regimens. The policy on salvage regimens in Indian centers also differ widely. In MCC we have been following this regimen for salvage in all relapsed/refractory treatment eligible lymphomas. Hence, we are trying to find out the treatment outcome of this salvage regimen in lymphomas.
To find out the efficacy and toxicity of GDP regimen as salvage chemotherapy in relapsed lymphomas.
In all treatment eligible cases of relapsed lymphomas treated with GDP salvage chemotherapy, to find out.
- Response rates
- Survival (PFS/OS)
- Treatment-related toxicity.
| Methods|| |
The study design involves retrospective observational cohort study.
All cases of relapsed lymphoma who received salvage chemotherapy with GDP or R GDP regimen. Cases treated between January 2011 to December 2017 will be included.
June 2018 to July 2018.
Data collection: Data will be retrieved from case records. Variables selected are demographic characteristics, type of lymphoma, characteristics at diagnosis (B, bulky, IPI/IPS), initial Rx, time to relapse from diagnosis, number and type of salvage chemo, and toxicity. Rx response outcome variable selected are response interim and response at the end of Rx, transplanted or not, date of progression, and date of death. If transplanted, CD 34 count and use of plerixafor will be documented. If died cause of death will be noted.
Data entry will be done in Excel. Continuous variables will be described in terms of either mean ± SD or median (IQR) depending on the statistical distribution of data. Categorical variables will be summarized in terms of frequencies and percentages. Median follow-up will be calculated using the Kaplan–Meier (KM) curves by reversing event and censor codes. Overall survival will be calculated from the date of diagnosis to date of death or date of the last follow-up. Progression-free survival will be calculated from the date of relapse to the date of progression or date of the last follow-up. Survival will be analyzed by KM curves and Cox proportional hazards (CPH) model or log-rank test. Data will be analyzed using SPSS version 20.
| Expected Results|| |
We may be able to derive at the response rates of this outpatient-based regimen in our setting.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]