Hodgkin's Disease Patients Research Articles

Long-term Outcome of Hodgkin Disease Patients Following High-Dose Busulfan, Etoposide, Cyclophosphamide, and Autologous Stem Cell Transplantation

Busulfan (Bu)-based preparative regimens have not been extensively investigated in Hodgkin disease (HD). The purposes of this study were to investigate the toxicity and efficacy of a novel preparative regimen of Bu 14 mg/kg, etoposide 50-60 mg/kg, and cyclophosphamide 120 mg/kg in patients with primary refractory and relapsed HD. One hundred twenty-seven patients with a median age of 33 years (range, 14-67 years) underwent transplantation. The regimen was well tolerated, with 5.5% treatment-related mortality at 100 days after transplantation. With a median follow up of 6.7 years, the 5-year progression-free survival was 48 ± 5%, and the 5-year overall survival was 51 ± 5%. A Cox proportional hazards model identified refractory disease at time of transplantation as the only significant factor affecting relapse and overall survival, whereas disease bulk >10 cm affected overall survival. Five patients died between 5.3 and 9.3 years of late complications, including secondary myelodysplasia or acute myeloid leukemia, secondary solid malignancies, and pulmonary toxicity. This novel Bu regimen is comparable to other radiation-free preparative regimens in its effectiveness in the control of HD and with a low-risk of early treatment-related mortality.

A Mobilizing Regimen of AMD3100 and G-CSF Increases Stem Cell Collection in Patients with Hodgkin's Disease, and PK Is Similar to That of Non-Cancer Patients.

For patients undergoing autologous peripheral blood stem cell transplantation (PBSCT), the number of CD34+ cells collected is a reliable predictor of neutrophil and platelet engraftment after transplantation, with doses > 5 x 106 CD34+ cells/kg associated with faster count recovery. Unfortunately, collection of an adequate number of peripheral blood stem cells (PBSCs) can be difficult in Hodgkin's disease (HD) patients. AMD3100 reversibly inhibits the binding of stromal cell-derived factor 1 (SDF-1), constitutively expressed on bone marrow stromal cells, to its receptor CXCR4, expressed on CD34+ cells. AMD3100 combined with G-CSF has been shown to improve PBSC collection compared to mobilization with G-CSF alone in patients with multiple myeloma or non-Hodgkin's lymphoma (Blood 2005; 106:1867). This study was undertaken to determine whether a mobilization regimen of AMD3100 + G-CSF can safely and effectively mobilize PBSCs in patients with HD who are undergoing autologous PBSCT. Results were compared to a historical control group comprised of 98 consecutive HD patients who underwent G-CSF-alone mobilization at our institution. Patients were followed post-transplant to evaluate engraftment timing and durability. Pharmacokinetic (PK) determinations were completed in a subset of patients (n=6) following the first dose of AMD3100. To date, 19 patients with relapsed (17) or refractory (2) HD have been mobilized with G-CSF (10 ug/kg/d) + AMD3100 (240 ug/kg/d sc at 10 p.m. beginning on day 4). Apheresis was performed 11 hours after each AMD3100 dose. The first dose of AMD3100 produced a median (range) 3.0 (1.9–12) fold increase in the number of circulating CD34+ cells. Twelve patients (63%) achieved a collection of ≥ 5 x 106 CD34+ cells/kg, a significantly higher proportion than historical controls (15%, p=0.049). Eighteen patients (95%) mobilized with AMD3100 + G-CSF collected > 2 x 106 CD34+ cells/kg (range, 0.9–9.6 x 106 CD34+ cells/kg), compared to 78% of controls (p=0.116). The median (range) number of apheresis procedures performed per patient was 2 (1–5). The median collection in the first two days of pheresis was 5.0 x 106 CD34+ cells/kg, which is significantly better than historical controls, who collected a median 3.0 x 106 CD34+ cells/kg in the first two days of pheresis (p=0.002). No grade II-IV adverse events were ascribed to AMD3100. Eighteen patients were transplanted with G-CSF + AMD3100 mobilized cells. All had prompt and stable engraftment, with median neutrophil recovery at day +9 (8–11) and median platelet recovery at day +15 (9–20). PK studies demonstrated that AMD3100 was rapidly absorbed following subcutanetous injection, with a median (range) Cmax of 0.87 (0.66–1.16) ug/ml. Plasma concentrations declined in a bi-exponential manner, with a median elimination half-life of 3.7 (2.4–4.0) hours. The median AUC0–infinity was 3,749 (2,808–4,761) ug-hr/ml. AMD3100 pharmacokinetics in this patient population are consistent with results previously obtained from healthy volunteers in the absence of G-CSF. We conclude that AMD3100 + G-CSF is a well-tolerated and effective mobilization regimen in patients with HD. For these patients, AMD3100 + G-CSF can improve the number of PBSCs collected and decrease the number of days of pheresis.

Final Results of a Large, Community Based Study Evaluating the Impact of First and Subsequent Cycle Pegfilgrastim on Neutropenic Events in NHL and HD Patients.

Introduction: Most alterations to chemotherapy (CT) dose and schedule are due to neutropenic events, which mainly occur in the 1st cycle. A nationwide survey found that of 4522 patients (pts) with diffuse, aggressive non-Hodgkin's lymphoma (NHL) treated with CHOP-like regimens in community practice, 40% experienced CT dose reductions, and 24% experienced CT dose delays (Lyman 2004). The ability of pegfilgrastim to reduce complications of CT-induced neutropenia has been established in clinical trials for pts receiving moderately (Vogel 2005) and highly (Holmes 2002) myelosuppressive CT. This prospective, community-based study evaluated the efficacy of 1st cycle pegfilgrastim in pts with NHL receiving CT in community practice.Methods: Pts ≥ 18 yrs with cancers other than leukemia or MDS were eligible, including those with major comorbidities who are generally not eligible for clinical trials. Key exclusions were weekly CT and concurrent radiotherapy. Pts received pegfilgrastim 6mg ~24 hours after CT in each cycle (up to 8 cycles). Endpoints included neutropenic complications and CT dose reductions and delays. Additionally, average relative dose intensity (ARDI) was calculated for major standard regimens. Point estimates and 95% confidence limits (CL) are provided.Results: This open-label, single-arm study enrolled 2249 pts at 319 sites. Of these, 325 pts with NHL and 46 pts with Hodgkin's disease (HD) were included in the primary analysis set. The mean (SD) age was 65 (13) years for NHL pts and 41 (14) for HD pts. 69% of NHL pts and 26% HD pts had advanced (III–IV) disease, 90% of NHL pts and 98% of HD pts had ECOG status 0 or 1, and 31% of NHL pts and 26% of HD pts had major comorbidities (eg. vascular disease, diabetes). 49% of NHL pts received standard CHOP ± R (cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab) and 78% of HD pts received standard ABVD (bleomycin, dacarbazine, doxorubicin, vinblastine). Few pts experienced neutropenic complications (table). All serious adverse events were consistent with those observed in pts receiving myelosuppressive CT.Conclusions: These results represent ‘real-world' data as the only major entry criterion for pts was a confirmed diagnosis of malignancy. Pts in our study received myelosuppressive CT with very few neutropenia-related alterations in CT dose and schedule supporting the use of pegfilgrastim from the 1st cycle of CT. Use of pegfilgrastim allowed maintenance of RDI with minimal CT dose delays and reductions.Incidence % (95% CL)NHLHDHospitalization related to neutropenia in cycle 19 (6, 13)4 (0.5, 15)Hospitalization related to FN in cycle 16 (4, 9)0 (0, 8)FN in cycle 1 (ANC<0.5×109/L and temperature 38.2°C)8 (5, 12)0 (0, 8)Incidence of grade 3/4 neutropenia in cycle 137 (32, 42)4 (0.5, 15)Neutropenia-related IV antibiotic use in cycle 19 (6, 12)4 (0.5, 15)Neutropenia-related CT dose reductions in cycle 212 (1, 5)0 (0, 8)Neutropenia-related CT dose delays in cycle 212 (1, 5)0 (0, 8)ARDI (mean % [SD])2CHOP ± R every 21 days77 (23)ABVD every 14 days83 (26)1physician reported2standard reference dose and planned cycle length were used to calculate DI in the denominator of RDI

Improved Homing of Antigen-Specific T Cells to Hodgkin's Disease (HD) Tumor Cells by Forced Expression of CCR4 Receptor.

One crucial requirement for the success of any adoptive T cell transfer is that the effector T cells should migrate efficiently to the tumor site. Such an effect has been documented following adoptive transfer of Epstein-Barr virus specific cytotoxic T cells (EBV-CTLs). Antigenic stimulus from (normal and malignant) cells persistently infected with EBV led to expansion and sustained survival, and was also associated with activity against the EBV+ HD tumors. Since most HD patients have tumors that are EBV- but CD30+, we attempted to extend this approach by incorporating a CD30 chimeric receptor (CD30CAR) into the EBV-CTLs. Pre-clinical animal studies showed that CD30CAR+ EBV-CTLs readily migrated to EBV+/CD30+ tumors, but had limited capacity to localize to EBV−/CD30+ tumor cells. The likeliest explanation for this observation is that EBV- HD tumors produce the chemokine TARC, which attracts Th2 and regulatory T cells, but has little effect on EBV-CTLs, since these express low levels of the TARC receptor, CCR4. We hypothesized that forced expression of CCR4 by redirected EBV-CTLs would improve their homing to the EBV−/CD30+ HD cells. The full length of CCR4 receptor was cloned into the SFG retroviral vector and used to transduce both activated T cells and EBV-CTLs obtained from 6 and 4 healthy donors, respectively. Expression of CCR4 was 12±8% on activated T cells (mainly on CD4+ cells, 12±6%) and 4±5% on EBV-CTLs. After transduction with a CCR4, but not a control vector, expression of CCR4 increased to 53±24% (CD4+ 27±15% and CD8+ 17±9%) on activated T cells and 30±19% on EBV-CTLs. We then evaluated the capacity of control and transgenic T cells and EBV-CTLs to migrate in response to TARC, using a trans-well migration assay. Migration was tested against different CD30+ tumor lines producing TARC at low (Karpas wild type, <32 pg/ml) or high levels (Karpas engineered to produce TARC, HDLM-2 and L428, all TARC >2000pg/mL), measured by ELISA. The percent of cells migrating in the trans-well assay was significantly increased for CCR4 transgenic CD8+ selected T cells (54±11% with Karpas/TARC vs. 8±2% with media vs. 8±4% with Karpas-wt). Migration of control OKT3/28 blasts was less than 15% in all the conditions. Migration was significantly inhibited by the addition of antibody blocking TARC (<10%). An improved migration of CCR4+ CD8+ cells was observed also towards HDLM-2 (48±7%) and L428 (45±16%) as compared to control T cells (21±7% and 23±7%, respectively). Similarly, CCR4+ EBV-CTL showed improved migration towards Karpas/TARC (26±14%) as compared to Karpas/wt (12±8%) or media (10±7%). This genetic modification did not modify either the phenotype or the antigen specificity of EBV-CTLs, which retained the capacity to kill autologous EBV+ lymphoblastoid cells. We then determined if forced expression of CCR4 receptor was functional in vivo. To track homing of transgenic T cells, we transduced them with the FireFlyluciferase (FFLuc) vector and followed signal with a bioluminescent system (IVIS, Xenogen). Sublethally irradiated SCID mice were implanted s.c. with Karpas/wt on the left side and Karpas/TARC on the right side. When tumors were measurable, FFLuc+CCR4+ T cells were injected iv. By 24 hours post injection, signal was detectable only at the side of TARC secreting tumor cells, and signal persisted at 10 to 16 fold higher levels on the TARC+ side for >7 days. These data suggest that the migration of CARCD30 EBV-CTL to EBV−/CD30+ HD can be augmented by co-expressing the CCR4 receptor.

Nutrition and Cancer: An Epidemiological Study in France. Focus in Hematology.

An epidemiological study was performed over a single day in France in 28 centers in 24 distinct cities, with, as a primary endpoint, an overview of the nutritional status and nutritional care of cancer patients over 18. This study involved 2068 patients (879 female, 1189 male), 100 investigators and 86 clinical departments, including hematology departments with 419 patients corresponding to 21% of the studied population either hospitalized or ambulatory. Among the total population for patients aged from 18 to 74 and patients over 75 years old, the body mass index (BMI) was 18.5 for 12.2% and 25.9% of cases, 18.5–25 for 50.7% and 36.4%, ≥25 for 37.2% and 37.7%. Weight loss since diagnosis of the malignant disease was between 0 and 5% for 33% of cases, 5 to 10% for 19%, 10 to 15% for 13%, 15 to 20% for 9%, > 20% for 10%. The nutrition risk index (NRI) was <83.5 for 22.5% of cases implying high risk of complications during hospitalization, between 83.5 and 97.5 for 37.3% with moderate complication risk and > 97.5 for 40.2% with no risk of complications. Among 1903 patients evaluated, 39% of patients presented severe malnutrition estimated by a BMI ≤18.5 (18–74 years) / BMI ≤21 (≥75 years) or a weight loss ≥10% of initial weight before hematological malignancy diagnosis. When we considered the performans status (PS), there was a correlation between PS and malnutrition with 14% of malnourished patients for PS 0 (n=388), 31.4% for PS 1 (n=560), 52.3% for PS 2 (n=451), 54.6% for PS 3 (n=249) and 65.3% for PS 4 (n=124). Among 377 patients who presented a hematological malignancy, 1/3 of them (34%) presented severe malnutrition (37% for females and 32% for males), as measured by BMI+weight loss. The prevalence of malnutrition was particularly high in patients harboring lymphoid malignancies: 48% of ALL patients (n=31), 39% of B- and T-NHLs (n=108), 36% of myeloma patients (n=69), 44% of CLL patients (n=16) and 13% of Hodgkin's disease patients (n=15). This is probably related to the addition of steroids in most of the standard chemotherapy treatments used in these malignancies that worsen the malnutrition already induced by the tumor. However, in myeloid malignancies severe malnutrition was observed in a quite large proportion of patients as well: 25% severe malnutrition of AML patients (n=118), and 11% for CML patients (n=9), and 55% (other, n=11). Among all the severely malnourished patients, 35.3% of patients did not receive any nutritional support and 34.1% were re-nourished (30.5% unknown). In the cancer patients harboring hematological malignancies (n=143) who received nutritional support, 25.9% had enteral nutrition, 39.9% parenteral nutrition, and 53.8% oral supplements with 65.2% compliance. This one-day epidemiological study points out that one third of the cancer patients harboring hematological malignancies present severe malnutrition that may favor infectious complications, impair the dose-intensity of chemo-radiotherapy, prolong intervals between chemotherapy courses, and alter the quality of life of patients. It underlines the absolute requirement for optimal nutrition care in these patients.

AMD3100 Plus G-CSF Mobilizes the Majority of Non-Hodgkin's Lymphoma (NHL), Multiple Myeloma (MM), and Hodgkin's Disease (HD) Patients Who Failed Prior Mobilization with Other Regimens.

Background: AMD3100, an inhibitor of SDF1 binding to CXCR4, synergizes with G-CSF to allow mobilization of sufficient CD34+ cells/kg for autologous transplantation in pts unable to collect adequate CD34+ cells with G-CSF alone. Therefore, a single patient use (SPU) protocol for AMD3100 was adopted for more than one patient entry per site and termed Compassionate Use Protocol (CUP). The only difference of standard of care was the addition of AMD3100 to a G-CSF mobilization on the evening prior to each day of apheresis. Pts who could not proceed to apheresis due to low peripheral blood counts or pts who did not collect a minimum of 2 × 10^6 CD34+ cell/kg were eligible.Methods: Overall, more than 280 patients with proven poor mobilization including 137 NHL, 73 MM, and 31 HD have been included in CUP. A data audit was performed to validate data from pts with either non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Hodgkin's Disease (HD). Sites were selected based on most patients entered, >3 of all diseases entered at a site, and sites conducting an AMD3100 trial. Audit included all pts, regardless of success or failure of the outcome; all information was collected on CRFs. Success of outcome was collection of ≥ 2×10^6 CD34+ cells/kg during the CUP procedure. CUP apheresis was done on day 5 after G-CSF (10mg/kg SC QD) and AMD3100 (240mg/kg SC Q10 PM) starting day 4.Results: Charts and CRFs were available for review for 115 pts; 63 (55%) were NHL patients from 29 sites, 35 (30%) were MM from 23 sites and 17 (15%) were HD from 13 sites. Of these pts, 58% were male, the median age was 59 years (range 21–77), 88% were Caucasian, and patient weight ranged from 43–128 kg. Prior treatments included a median of two regimens of chemotherapy in each of the three groups. Safety was generally favorable with no drug-related SAE's and with an AE profile similar to that seen in research trials. The rates of successful collection of ≥ 2×10^6 CD34+ cells/kg per disease state as well as prior mobilization regimen are summarized in table 1. The median number of mobilizations for the successful patients was 3 days for NHL and HD and 4 for MM. Eighty-eight of the patients underwent transplantation with any cells. For example, of the 47 NHL patients transplanted, 24 had CUP only cells and 23 had mixed cells. The median number of days to engraftment was 11 for PMN and 18 for platelets. Long term follow up is limited, but there do not appear to be graft failures. At least 12 of the pts have died.Conclusions: AMD3100 in a poor mobilizer population is generally safe and well tolerated and is very effective in mobilizing > 2×10^6 CD34+ cells/kg.Mobilization success rate by disease state: overall and prior mobilization regimenOverallPrior CytokinePrior ChemotherapyNHL60%53%68%HD76%78%75%MM71%73%71%

Analysis of Donor Age and Absolute Lymphocyte Count Recovery as Prognostic Indicators of Survival after Allogeneic Blood or Marrow Transplantation.

Absolute lymphocyte count (ALC) recovery ≥500 cells/mL at day 15 or 30 post-autologous (autoBMT) transplantation has been reported in many studies as an independent prognostic indicator of overall survival (OS) and progression free survival (PFS) in non-Hodgkin lymphoma (NHL), Hodgkin Disease (HD), multiple myeloma (MM) and breast cancer patients. ALC recovery has also been reported in the allogeneic blood and marrow transplant (alloBMT) setting as an important factor in predicting risk of relapse of acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). It has been shown in previous reports that donor age is critically important for OS after alloBMT. In addition, increased donor age correlates with a reduction of common lymphoid progenitor (CLP) differentiation potential which led us to hypothesize that donor age might predict ALC recovery time in related and unrelated alloBMT recipients. We reviewed 76 related and 36 unrelated HLA-matched consecutive patients with hematological malignancies who underwent first alloBMT at Roswell Park Cancer Institute between 4/20/2000 and 3/17/2006. The patient population included 53 males and 59 females with a median (range) age of 44 (4–68) years. Conditioning regimens were FluMel (n=33), CyTBI (n=32), BuCy (n=19), FluCy (n=13), VCT (n=11), and other (n=4). The stem cell source was bone marrow (n=34), peripheral blood (n=77) or both (n=1). Hematologic engraftment was defined as absolute neutrophil count (ANC) reaching 500 cells/ml or more for 3 consecutive days. ALC at day 30 and time to ALC ≥ 500 cells/mL were analyzed. Our results show that peripheral blood (p=0.04) and a higher CD34+ dose (p=0.05) were significantly associated with day 30 ALC ≥ 500. Time to ALC recovery ≥500 cells/mL was not significantly related to donor age for related alloBMT (p=0.340). However, in unrelated alloBMT patients, there was a trend toward increasing donor age associated with a longer time to ALC recovery ≥ 500 cells/mL (p=0.087). ANC recovery correlates with ALC recovery in related (R=0.237, p=0.02) and unrelated (R=0.514, p<0.001) alloBMT recipients. Recipient and donor age were strongly correlated in related alloBMT patients (R=0.89, p<0.001) and weakly correlated in unrelated alloBMT patients (R=0.236, p=0.09). ALC recovery ≥ 500 at day 30 post alloBMT was not a significant predictor of OS in either the related or unrelated subgroups. We will further examine donor-recipient age disparities in unrelated alloBMT patients and present multivariate analyses of predictors for time to ALC recovery.

Routine Use of PET Scans After Completion of Therapy in Pediatric Hodgkin Disease Results in a High False Positive Rate

Fluoro-2-deoxy-D-glucose positron emission tomography scans are becoming standard of care in the evaluation of Hodgkin disease (HD). The frequency of false positive (FP) PET scans in pediatric HD after completion of therapy has not been well studied. All PET scan reports on pediatric HD patients at our institution between February 2000 and February 2005 were retrospectively reviewed. Scans were considered positive if the interpretation was most consistent with malignancy. FP results were determined by pathologic evaluation, resolution on scan, or absence of disease progression over at least 1 year without intervention. We reviewed 255 PET scans on 47 patients, including 156 posttherapy scans on 34 patients. Positive predictive value for scans obtained during routine follow-up was 11%, with an FP rate of 16%. Identifiable etiologies of FP scans included: fibrosis, progressive transformation of germinal centers, abdominal wall hernia, appendicitis, thymus and HIV associated lymphadenopathy. Routine PET scans after completion of therapy in pediatric HD patients have a low positive predictive value and a high FP rate. Prospective studies are needed to reduce the ambiguity of positive results. In the interim, positive PET scans after treatment should be interpreted cautiously and therapeutic decisions should not be made without histologic confirmation.

Treatment options in relapsed or refractory Hodgkin disease patients: the mini‐BEAM regimen does exist too

Treatment options in relapsed or refractory Hodgkin disease patients: the mini‐BEAM regimen does exist too

Early positron emission tomography (PET) restaging: a predictive final response in Hodgkin's disease patients

Background: It is important to distinguish between responders to standard treatment and non-responders Hodgkin's disease (HD) patients.Patients and Methods: Between June 2003–September 2004, in our institute, 40 newly-diagnosed patients with advanced stage HD were consecutively treated with ABVD chemotherapy for six cycles. All these patients underwent staging/restaging: computed tomography (CT) and positron emission tomography (PET) at time 0, PET after two cycles, CT and PET after four and six cycles.Results: After two cycles (PET-2), the PET was negative in 28/40 (70%), positive in 8/40 (20%), and minimal residual uptake (MRU) was present in the remaining four (10%) patients. After treatment, among eight patients who were PET-2+, seven showed refractory disease and one had relapse after 3 months. All four patients with MRU at the PET-2 became PET_ during the further four cycles and, after treatment, three were in complete response (CR) and one relapsed after 5 months. All 28 PET negative patients at the PET-2 remained PET negative and all of them were in CR after treatment.Conclusions: The PET use for early (after two cycles) response assessment in HD patients is a significant step forward and has the potential to help physicians make crucial decisions about further treatment.

FDG-PET/CT predicts outcome in patients with aggressive non-Hodgkin’s lymphoma and Hodgkin’s disease

Early therapy response assessment with metabolic imaging is potentially useful to determine prognosis in aggressive lymphoma and, thus, can guide first-line therapy. Forty-eight patients with aggressive lymphoma [24 Hodgkin's disease (HD); 24 non-Hodgkin's lymphoma (NHL)] underwent fluoro-deoxyglucose positron emission tomography (FDG-PET) before chemotherapy (PET1) and at mid-treatment (PET2). Therapeutic response was evaluated using conventional methods at mid-treatment. PET2 results were related to event-free survival (EFS) and overall survival (OS) using Kaplan-Meier analyses. PET1 was positive in all patients. PET2 was negative in 38 patients (18 NHL-20 HD) and positive in 10 (6 NHL-4 HD). Of the PET-negative patients, 61 and 65% achieved complete remission, and only 50 and 25% of PET-positive patients, respectively, for NHL and HD, achieved complete remission. Significant associations were found between PET2 and EFS (p = 0.0006) and OS (p = 0.04) for NHL, and EFS (p < 0.0001) for HD (but not for OS, because no HD patient died). FDG-PET at mid-treatment can predict the outcome of patients with aggressive lymphoma and should be a useful tool to modify an ineffective therapy.

Clinical features and correlates of gemcitabine‐associated lung injury

Gemcitabine is a commonly used chemotherapeutic agent structurally and pharmacologically similar to cytarabine. Recently, instances of severe gemcitabine-associated lung injury have been reported. Herein, investigators affiliated with the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program evaluated clinical characteristics of gemcitabine-associated severe acute lung injury from clinical trial reports, medical literature case reports, and spontaneous reports to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). Clinical data were obtained by reviewing adverse event case reports for gemcitabine-associated lung injury as reported in the medical literature and in the FDA AERS database. Upper limit estimates of ADE rate were derived from review of published clinical trials reporting gemcitabine-associated lung injury rates of 10% or higher. A total of 178 reports of gencitabine-associated lung injury were identified; in AERS, there were 55 cases from clinical trials and 92 spontaneous reports. A comprehensive search revealed 31 medical literature reports. Clinical features of gemcitabine-associated lung injury included dyspnea, fever, pulmonary infiltrate, and cough with recognition of toxicity occurring after a median duration of 48 (range, 1-529) days after initiation of gemcitabine. The taxanes, docetaxel and paclitaxel, were frequently reported as coadministered therapies. Eleven Phase II or Phase III clinical trials with 317 patients identified gemcitabine-associated lung injury rates of greater than 10%, with the highest rates (22% and 42%) being observed in Phase III clinical trials where Hodgkin disease patients were treated with a regimen that included gemcitabine and bleomycin. High rates of gemcitabine-associated severe lung injury were observed when gemcitabine was combined with other therapies known to also cause lung injury. Physicians should have a high index of suspicion for this toxicity and report the relevant clinical findings to the FDA's AERS.

Clinical relevance of soluble HLA-I and β2-microglobulin levels in non-Hodgkin's lymphoma and Hodgkin's disease

Plasma levels of beta-2 microglobulin (β2M), a subunit of the human leukocyte antigen-class I (HLA-I) molecule, correlate negatively with outcome in non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). We examined the clinical relevance of soluble HLA-I (sHLA-I) levels in NHL and HD. Sera from consecutive NHL ( n = 65) and HD ( n = 37) patients were analyzed in a blinded manner. NHL and HD patients had significantly higher levels of sHLA-1 and β2M than control subjects. In NHL patients, sHLA-I levels correlated with clinical behavior in a fashion similar to that of β2M. However, multivariate analysis incorporating β2M, sHLA-I, and international prognostic index (IPI) indicated that NHL patients with elevated (>312.6 μg/100 mL) sHLA-I levels had significantly shorter survival, independent of IPI score as well as β2M. In HD patients, β2M but not sHLA-I levels were associated with clinical behavior. These findings not only establish the role of sHLA-I as an independent tumor marker in NHL that can be used to stratify patients, but also suggest that β2M and sHLA-I may reflect different biological processes in HD and NHL. Further studies are needed to assess whether the immunomodulatory properties of sHLA-I may be responsible for its divergence from β2M as an indicator of clinical behavior in HD.

Pegfilgrastim alone or with ciproflaxin significantly reduces febrile neutropenia and hospitalization vs G-CSF alone in breast cancer patients receiving neoadjuvant chemotherapy with docetaxel/doxorubicin/cyclophosphamide (TAC)

Hodgkin's disease is considered a curable disease. The use of appropriate staging techniques and treatment methods has resulted to long-term cause-specific survival rates as high as 90% in early stages, 75% or greater in advanced stages. Long-surviving Hodgkin's disease patients, however, face new problems which have become apparent as greater numbers of successfully treated patients are followed for longer periods of time. These problems mostly concern chronic medical as well as psychosocial complications which can interfere with survivors' quality of life. Specific therapy may result in severe infections, thyroid, cardiovascular, pulmonary, digestive or gonadal dysfunction. It may also result in secondary malignancy which is considered the most serious complication. Because the vast majority of patients who achieve remission will remain symptom-free and do enjoy a normal life, long-term follow-up should concentrate on prevention and early detection of treatment-related complications and of secondary malignancy.

AMD3100 + G-CSF improves hematopoietic progenitor cell (HPC) collection in patients with hodgkin’s disease (HD)

Autologous stem cell transplantation is indicated for patients with HD who have primary refractory disease or who relapse after a first remission. For these patients, as for other patients undergoing autologous transplantation, the number of CD34+ cells infused is a reliable predictor of neutrophil and platelet engraftment, and doses ≥ 5 x 10 6 CD34+ cells/kg are associated with faster count recovery. However, among the 98 patients with HD who have undergone G-CSF-alone mobilization at our institution in the past five years, 22% did not achieve a minimum HPC collection of 2 x 10 6 CD34+ cells/kg in ≤ 5 apheresis procedures, and only 15% achieved a collection ≥ 5 x 10 6 CD34+ cells/kg. AMD3100 mobilizes HPCs by reversibly inhibiting the interaction of CXCR4 and SDF-1α. It has been shown to improve HPC mobilization in patients with multiple myeloma and non-Hodgkin’s lymphoma. Here we present results for the first ten HD patients treated with a mobilization regimen of AMD3100 + G-CSF. To date, ten patients with relapsed (8) or refractory (2) HD have been mobilized with G-CSF (10 ug/kg/d) + AMD3100 (240 ug/kg/d) beginning on day 4. Apheresis was performed 11 hours after each AMD3100 dose. The first dose of AMD3100 produced a median (range) 3.0 (1.9–5.1) fold increase in the number of circulating CD34+ cells. Six patients (60%) achieved a collection of ≥ 5 x 10 6 CD34+ cells/kg, and all patients collected > 2 x 10 6 CD34+ cells/kg (range, 3.6–9.4 x 10 6 CD34+ cells/kg). The median (range) number of apheresis procedures performed per patient was 2 (1–4). No grade II-IV adverse events were ascribed to AMD3100. Eight patients have been transplanted with G-CSF + AMD3100 mobilized cells. All have had prompt and stable engraftment, with median neutrophil recovery at day +9 (9–11) and median platelet recovery at day +20 (15–23). Two patients had very early engraftment, with absolute neutrophil count greater than 100 on day +7. We conclude that AMD3100 + G-CSF is a well-tolerated and effective mobilization regimen in patients with HD. All patients (100%, 95% CI 69%-100%) mobilized with AMD3100 + G-CSF achieved the minimum collection of 2 x 10 6 CD34+ cells/kg, and a significantly higher proportion of patients (60%, 95% CI 26%–88%) achieved the goal collection of ≥ 5 x 10 6 CD34+ cells/kg than did the historical controls (15%). Importantly, the median collection in the first two days of pheresis was 5.4 x 10 6 CD34+ cells/kg, which is significantly better than historical controls, who collected a median 3.0 x 10 6 CD34+ cells/kg in the first two days of pheresis (p=0.014). Our results demonstrate that the mobilization regimen of AMD3100 + G-CSF can improve the number of HPCs collected and decrease the number of days of pheresis in HD patients. This regimen will be pursued further in this patient population.

Granuloma annulare on herpes zoster scars in a Hodgkin's disease patient following autologous peripheral stem cell transplantation

Various cutaneous lesions including granulomatous reactions may occur at sites of resolved herpes zoster infection. A 46-year-old man with Hodgkin's disease developed localized granuloma annulare lesions on herpes zoster scars 3 months after allogeneic peripheral stem cell transplantation. This is the first case of granuloma annulare localized on herpes zoster scars that developed following peripheral stem cell transplantation.

High dose sequential chemotherapy and autologous stem cell transplantation in patients with relapsed/refractory lymphoma

Although high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL), more than 50% of patients will experience relapse following ASCT. High-dose sequential chemotherapy (HDSC) can intensify the conventional salvage treatment and improve the outcome of ASCT by maximal debulking of the tumor load with the use of non-cross resistant drugs, each at their maximal tolerated doses. We conducted a phase II study in 40 patients with relapsed/refractory HD (n = 18) and NHL (n = 22) using HDSC followed by ASCT. Only patients sensitive to salvage chemotherapy were eligible for the protocol, consisting of three phases. Phase I consisted of cyclophosphamide (4.5 g/m2) followed by G-CSF and peripheral blood stem cell (PBSC) collection. Phase II consisted of etoposide (2 g/m2). The transplant phase consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by PBSC infusion. Eleven out of nineteen patients with B-cell lymphoma received rituximab. Prior to HDSC, 45% of the patients were in complete remission (CR) and 55% were in partial remission (PR). After completion of all phases of the protocol, 35 out of 39 evaluable patients achieved CR (90%) and this was durable in 30 (75%) patients with a projected progression-free survival (PFS) rate at 4 years of 71.7%. Treatment-related mortality rate at day +100 was 2.5% (n = 1). At a median follow-up of 32 months (range, 3 – 61), nine patients relapsed/progressed and eleven patients died. The estimated 4-year PFS and overall survival (OS) were 72.2% and 47.6% in HD patients and 70.3% and 69.4% in NHL patients, respectively. Factors predicting OS were response to conventional salvage therapy and stage prior to salvage therapy. When compared to patients achieving PR, patients who attained CR prior to HDSC had a significantly higher probability of 4-year OS (78.4% vs 31.3%, p = 0.02). Three prognostic subgroups were defined according to the score determined by stage prior to initiation of salvage chemotherapy, remission duration prior to salvage (refractory/early relapse vs. late relapse) and response to salvage. Prognostic score was found to predict OS, PFS and event free survival (EFS). In conclusion, HDSC followed by ASCT is an effective salvage therapy with acceptable toxicity, allowing further consolidation of response attained by conventional salvage therapy.

Is CT scan still necessary for staging in Hodgkin and non-Hodgkin lymphoma patients in the PET/CT era?

Background: The clinical impact of fused PET/CT data on staging and patient management of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) was assessed.Patients and methods: A total of 103 consecutive patients with newly diagnosed NHL (n = 68) and HD (n = 35) were assessed retrospectively. Three comparisons were carried out in an attempt to assess the added value of each modality.Results: For NHL patients, there were significant differences between staging by CT versus PET/CT (P = 0.0001). Disease was upstaged by PET/CT in 31% (mostly in stages I and II) and downstaged in only 1% of patients. In 25% of the patients, the treatment approach was changed according to CT versus PET/CT findings. For HD patients, disease was upstaged by PET/CT in 32% and downstaged by PET/CT in 15% (P = NS). As for NHL, upstaging by PET/CT versus CT was evident mostly for stages I and II. The treatment strategy was altered as determined by CT versus PET/CT in 45% of the patients.Conclusions: The addition of PET/CT to CT changed the management decisions in approximately a quarter of NHL and a third of HD patients, mostly in early disease stages. Thus, PET/CT performed as the initial staging procedure may well obviate the need for additional diagnostic CT in the majority of patients.

Clinico-Pathological Study of Hodgkin's Disease in King Abdulaziz University Hospital, Jeddah

Abstract Hodgkin's disease (HD) has unique epidemiological features with diversified pathologies. The aim of this study was to investigate the clinicopathological pattern of HD at King Abdulaziz University Hospital (KAUH), Jeddah. Our results will be compared to those in the literatures. In addition, the relationship between peripheral blood lymphopenia on presentation, and clinical and laboratory variables among HD patients will also be addressed. A total of 81 HD patients were included in this study. The records were analyzed retrospectively from January 1998 through December 2004 and recorded in a structured form. In order to determine the importance of lymphopenia on presentation as a diagnostic marker in HD a comparison was made to a similar number of patients with non-Hodgkin's lymphoma (NHL) after standardization for age, sex and clinical presentation. Moreover, the association between lymphopenia and clinical and laboratory variables were also studied. There were 54 (66.7%) non-Saudi and 27 (33.3%) Saudi patients with a male to female ratio of 1.3:1. The mean age of the patients was 40.4 years, ranging from (12–82) years with a SD of ±18.95. Cervical lymph nodes were the most common finding at the time of presentation. Mixed cellularity was the most frequent pathology followed by nodular sclerosis with prevalence of advanced stages of the disease in 48 (59.2%) and B symptoms 67 (82.7%). Lymphopenia was seen in 33 patients, 24 (72.7%) of them were above the age of 30. A comparison between Hodgkin's disease and non-Hodgkin's lymphoma regarding lymphopenia, using the same number of patients after standardization for age, sex and presentation did not turn out to be significant (P > 0.05). Relationship between lymphopenia and other clinical and laboratory variables also did not turn out to be significant with the exception of anemia where the P-value was

Treatment of Hodgkin's Disease: A Twenty-Year Follow-up of Patients at a Center in Korea

Hodgkin's disease (HD) is a hematologic malignancy which shows common features regardless of race, but racial differences may be considered with certain clinical characteritcs. HD in Korea shows somewhat different characteristics when compared to cases in Western countries. We evaluated the clinical and histopathologic characteristics of HD, the outcomes of various chemotherapy regimens, and prognostic factors of HD in Korea. One hundred and five patients with initial histopathologic diagnosis of Hodgkin's disease were retrospectively reviewed 20 years after diagnosis at Yonsei University College of Medicine. Nodular sclerosis was the most common histopathogic subtype (41%) and mixed cellularity was nearly as common (40%). The overall complete remission rate (CR) was 87.6%. The disease-free survival (DFS) and overall survival (OS) rate were 79.2% and 84.8% at 5-years, 70% and 79.2% at 10- and 20-years. There were no significant differences in CR rate and DFS, but OS rates were significantly higher in m-BACOP and ABVD regimen. Univariate analysis revealed that age, B-symptom, ECOG scale, Ann Arbor stage, international prognostic index, and serum β2-microglobulin level were significant prognostic factors for both DFS and OS. Multivariate analysis demonstrated that age, B symptoms, and ECOG scale were significant prognostic factors for OS only. In conclusion, the survival rates of HD patients in our center were superior to those of previous reports in Korea and Western countries. Considering the higher OS rate and decreased incidence of side effects, the ABVD regimen may be recommended for the initial treatment of Hodgkin's disease.