Chemotherapy For Stem Cell Mobilization Research Articles

Biosimilar G-CSF Versus Originator G-CSF for Autologous Peripheral Blood Stem Cell Mobilization: A Comparative Analysis of Mobilization and Engraftment

Biologic agents are among the fastest-growing classes of therapeutic products. A biosimilar therapeutic product is defined as one that is similar to an already licensed reference product in regard to quality, safety, and efficacy and is often priced more competitively (Expert Committee on Biological Standardization, 2009; Publicover, et al., 2013).In 2016, the Saskatchewan Cancer Agency effectively changed from a granulocyte colony-stimulating factor (G-CSF) brand name product (Neupogen®) to a biosimilar (Grastofil®) for stem cell mobilization prior to autologous stem cell transplants (ASCT). However, because its efficacy in this setting is currently unknown, many institutions continue to use the brand name product. To address this, we reviewed patient charts and compared the efficacy of CD34+ collection in 170 patients who received Neupogen® and 47 patients who received Grastofil® between 2012 and 2018.Additionally, we analyzed efficacy of mobilization with both G-CSF products either alone or in combination with chemotherapy, patients requiring more than one apheresis day and requirement for Plerixafor®. Time to engraftment, and length of stay in hospital post ASCT were used as clinical efficacy parameters. This analysis is important to ensure that patient outcome is not compromised upon use of Grastofil® as opposed to the already approved reference, Neupogen®. The increased use of biosimilars would allow for decreased costs and more sustainable healthcare.ResultsNeupogen® and Grastofil® had similar efficacy for stem cell mobilization as 92.4% of the patients harvested with the brand name had a successful harvest compared to 100% of the patients given the biosimilar. A successful harvest is defined as a collection of ≥2x106 CD34+ cells for patients planned for one stem cell transplant and ≥4x106 CD34+ cells for patients planned for two transplants. Additionally, the two drugs did not display a statistically significant difference in Plerixafor requirement in a situation with low CD34+ count. Amongst all 217 patients, 25.9% of patients given Neupogen® required Plerixafor® as compared to 23.4% of Grastofil® patients.As seen from Table 1, by using the Wilcoxon test to compare the efficacy of Neupogen® and Grastofil® without chemotherapy for stem cell mobilization, there was no significant difference seen with a p-value of 0.53. Similarly, in patients mobilized with chemotherapy in addition to either Neupogen® or Grastofil®, similar efficacy was seen between the groups given a p-value of 0.95.There was no statistically significant difference between the patient groups with respect to requiring more than 1 day of apheresis. 59.4% of patients mobilized with Neupogen® required more than 1 apheresis day compared to 76.9% of Grastofil® patients (p = 0.11). Similarly, of the Neupogen® and Grastofil® groups mobilized with chemotherapy, 42.5% and 38.1%, respectively, required more than one apheresis day which was not statistically different (p = 0.71). Table 2 presents the engraftment data which also suggests that the two drugs behave with similar efficacy in this respect.Length of stay in hospital post autologous stem cell transplant was an additional variable analyzed. Again, there was no significant difference in length of stay between patients who received Neupogen® (median=18.5 days, IQR=17.0-21.0) or Grastofil® (median=19.0 days, IQR =17.0-22.0) without chemotherapy (p = 0.75). When chemotherapy was added to the mobilizing regimen, lengths of stay post autologous stem cell transplant increased but there was no statistically significant difference in length of stay between Neupogen® plus chemotherapy mobilization (median=22.0, IQR =20.0-26.0) versus Grastofil® plus chemotherapy (median=24.0 days, IQR =21.0-29.0) mobilization (p-value =0.10).In conclusion, when comparing the use of either a Neupogen® or Grastofil® based mobilization regimen in terms of stem cell harvest success, Plerixafor® use, more than one apheresis day required, time to engraftment, and length of stay in hospital, no significant difference was found indicating that both products, the reference agent and its biosimilar have similar efficacy. The use of such biosimilars can provide substantial cost savings to the health care system. [Display omitted] DisclosuresElemary:Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

In-Vivo Purging with Rituximab (R) Followed By Z/BEAM Vs BEAM/R Autologous Stem Cell Conditioning for Relapsed Diffuse Large B-Cell Lymphoma (DLBCL) Patients (pts): Mature Results from a Combined Analysis of 3 Trials

In-Vivo Purging with Rituximab (R) Followed By Z/BEAM Vs BEAM/R Autologous Stem Cell Conditioning for Relapsed Diffuse Large B-Cell Lymphoma (DLBCL) Patients (pts): Mature Results from a Combined Analysis of 3 Trials

Stem Cell Mobilization Chemotherapy with Gemcitabine Is Effective and Safe in Myeloma Patients with Bortezomib Induced Neurotoxicity

Background: Vinorelbine chemotherapy with G-CSF stimulation is a widely applied non-myelosuppressive mobilization regimen in Switzerland for myeloma patients, but its neurotoxic potential limits its use in patients with bortezomib induced polyneuropathy. Methods: In this single-center study, we alternatively evaluated safety and effectiveness of gemcitabine chemotherapy with G-CSF for mobilization of autologous stem cells. Results: Between 03/2012 and 02/2013, all bortezomib pretreated myeloma patients planned to undergo first-line high-dose melphalan chemotherapy received a single dose of 1250mg/m2 gemcitabine, with G-CSF started on day four. The 24 patients in this study have received a median of four cycles of bortezomib-dexamethason based induction. Bortezomib-caused polyneuropathy was identified in 21 patients (88%) by clinical evaluation and a standardized questionnaire. Administration of gemcitabine mobilization did not induce novel or aggravate preexisting neuropathy. Stem cell mobilization was successful in all 24 patients, with a single day of apheresis being sufficient in 19 patients (78%). The median yield was 9.51 x 106 CD34+ cells/kg. Stem collection could be accomplished at day 8 in 67%. Conclusion: Our data suggest that single-dose gemcitabine together with G-CSF is an effective mobilization regimen in myeloma patients and a safe alternative non-myelosuppressive mobilization chemotherapy for myeloma patients with bortezomib induced polyneuropathy. DisclosuresNo relevant conflicts of interest to declare.

Neurotoxicity of stem cell mobilization chemotherapy with vinorelbine in myeloma patients after bortezomib treatment

Vinorelbine chemotherapy with G-CSF stimulation is the standard mobilization regimen in Switzerland for multiple myeloma patients. However, with the increasing use of bortezomib during induction treatment, adding the neurotoxic compound vinorelbine for mobilization may aggravate bortezomib-induced polyneuropathy. In this retrospective single-center study, we aimed to explore vinorelbine mediated neuropathy in 106 consecutive bortezomib pretreated myeloma patients. We confirmed that vinorelbine with G-CSF represents a reliable and effective regimen for mobilization of autologous stem cells. However, the single administration of 35mg/m2 vinorelbine added significant neurotoxicity. We found that 24 patients (24%) reported vinorelbine mediated neurotoxicity: Aggravation of bortezomib-induced neuropathy was observed in 17 patients (17%), and vinorelbine mobilization induced first occurrence of polyneuropathy in additional 7 patients (7%). We observed that development of polyneuropathy was not associated with differing survival rates. Finally, affected patients reported polyneuropathy associated disease burden as “very high” in 13% and “high” in 50%. Our data indicate that a single administration of vinorelbine to mobilize autologous stem cells is associated with significant additional polyneuropathy in bortezomib pretreated myeloma patients. The efficacy of vinorelbine mobilization should be balanced against its neurotoxic potential.

Plerixafor plus G‐CSF in combination with chemotherapy for stem cell mobilization in a pediatric patient with Ewing's sarcoma

Some malignant tumors in childhood require high-dose chemotherapy with stem cell support to achieve a cure. In patients heavily pretreated with myelosuppressive chemotherapy or irradiation, granulocyte colony-stimulating factor (G-CSF) may fail to mobilize stem cells from the bone marrow. Based on the experience with lymphoma and myeloma patients in whom peripheral blood-derived stem cell (PBSC) collection following mobilization with G-CSF failed, we successfully employed plerixafor in a 14-year-old female diagnosed with Ewing's sarcoma in early relapse treated with three lines of chemotherapy in whom PBSC could not be mobilized using either G-CSF alone or G-CSF following chemotherapy. No side effects were observed. Plerixafor may be an effective and safe agent for stem cell collection in pediatric patients with solid tumors, although new studies addressed to evaluate its effectiveness and safety are needed.

Mature Results of BEAM/High-Dose Rituximab Vs BEAM/Yttrium-90 Ibritumomab Tiuxetan (Zevalin®) and Autologous Stem Cell Transplantation (ASCT) for Relapsed CD20+ Follicular and Diffuse Large B-Cell Lymphoma: Survival Outcomes and Risk of Secondary Malignancies

Abstract 2005 Background:The addition of high-dose rituximab (hR) has been shown to improve results for pts with relapsed CD20+ diffuse large b-cell (DLBCL) and follicular (FL) lymphoma who undergo high-dose chemotherapy (HDC) with BEAM (hR-BEAM) followed by ASCT (Khouri, J. Clin.Oncol, 2005). More recently, we and others reported upon the safety of incorporating the radio-labeled antibody Yttrium-90 Ibritumomab Tiuxetan (Zevalin®) to the BEAM conditioning (Z-BEAM). Herein, we compare the long-term outcomes, by histology, in 147 pts treated with these 2 regimens. Methods and Patients: Pts were treated on 2 consecutive trials. Both groups received R during stem cell collection with R administered at 375 mg/m2 on the day before initiating chemotherapy for stem cell mobilization, and again at 1000 mg/m2, 7 days later. Pts with hR-BEAM (n =111) received additional R at 1000 mg/m2 on days +1 and +8 after ASCT, as previously described. The Z-BEAM pts (n=36) received Zevalin® given at the fixed dose of 0.4 mCi/Kg on day –14 followed by HDC (days –7 to –1). There was no statistically significant difference in age, gender distribution, number of prior chemotherapies, stage, disease status (CR/PR), LDH and IPI at the time of transplant between the 2 groups. Serum b2- microglobulin level, was higher in the DLBCL pts who received R-BEAM than the Z-BEAM [median 2.3 vs 1.9, range 1.3–8 vs 1.2–6.5, respectively (p=.01). Both groups of pts were staged with CT, PET (whenever indicated) scans and marrow biopsies, every 3 months for the first year, every 6 months x5 years, then yearly thereafter. Results: A- DLBCL pts: Median follow-up for the DLBCL pts who received hR-BEAM (n=65) and Z-BEAM (n=25) was 97 months (range,17–122), and 56 months (range 34–78), respectively. OS at 5-year was 78% and 76%, respectively (p=0.7). PFS rates at 5-year were 78% for both. Within the R-BEAM group, PET status (expert review by H.M.) and LDH >nl at transplant were important prognostic factors for both OS {HR 4.9 and 5.9; p=0.001 for both) and PFS. IPI >1 was also determinant for PFS but not OS. We could not identify prognostic factors for OS in the Z-BEAM group; only advanced stage was found of importance for PFS. B-Follicular pts: Pts were considered for ASCT if they had no donors. Median follow-up for the FL pts who received hR-BEAM (n=46) and Z-BEAM (n=11) was 59 and 56 months, respectively. OS and PFS rates at 5-year were not statistically different [OS 77% vs 60%, (p=0.7), and PFS were 60% vs 45%, (p=0.4)}. The only determinant for both OS and PFS in the combined groups, was the number of prior chemotherapies of >2 prior transplant (HR 4.1 for OS, p=0.04; HR 2.5 for PFS, p=0.05). This confirms our earlier preliminary observation (ASH 2007). C. Secondary malignancies: All pts who received Z-BEAM, had routine cytogenetic analysis as well FISH for −7,-5 abnormalities performed on pre-transplant bone marrow samples. We found that the risk of secondary myelodysplasia or leukemia at 5-year to be 8% in both hR-BEAM and Z-BEAM. The risk of any other malignancies was also comparable (6% and 5%, respectively). Conclusions: Long follow-up analysis suggests that survival outcomes between Z-BEAM and hR-BEAM appear to be comparable, and that fixed dose Zevalin® of 0.4 mCi/kg can be added to BEAM without increasing the risk of secondary malignancies. DLBCL pts with PET+, or LDH> nl, or IPI>1 at transplant had inferior outcomes after hR-BEAM. Whether the addition of Zevalin® to the conditioning in this setting would improve outcomes is under investigation in a randomized trial at our center (protocol 2006–1018), using above prognostic factors for patients stratification. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

12-Year Experience with High-Dose Rituximab-Containing Autologous Stem Cell Transplantation for SOX11-Positive Mantle Cell Lymphoma Patients in First Remission: Emerging Lymphoma-Free Survival Plateau After 3 Years,

Abstract 4138 Background:The addition of high-dose rituximab to conditioning regimens has been shown to improve outcomes of autologous stem cell transplantation (ASCT) for mantle cell lymphoma (MCL) patients (pts) in first partial (PR) or complete remission (CR)(Tam C et al. Blood 2009,113:4144). It has been suggested that absence of SOX11 expression can identify a subtype of indolent MCL with excellent outcomes that might be managed more conservatively than conventional MCL. We now report updated results of ASCT for 40 MCL pts treated at our center between 05/99 and 10/10. We also report on SOX-11 expression in a subset of these pts. Methods and Patients:Pts had a median age of 54 years (range, 38–72), and 30% were older than 60 years. At diagnosis, 60% had IPI>1, 30% had intermediate/high MIPI, 88% had stage IV disease, and 78% had bone marrow involvement. 28% had blastic features and Ki-67 was ≥30% in 11/23 (52%) pts who were tested. Pts were treated with R-CHOP or R-hyper-CVAD × 4 cycles induction in 30% and 45% respectively (Group A). Since 2001, pts were referred to ASCT only if they failed to achieve CR with >4 cycles of R-hyper-CVAD induction (n= 10, 25%) (Group B). Prior to transplant, CR (or CR unconfirmed-CRu) was present in 62% pts; 38% were in PR, and 18% were PET+. Conditioning was R-BEAM and R-Cy-TBI conditioning in 77% and 23% respectively. Pts received R during stem cell collection with R administered at 375 mg/m2 on the day before initiating chemotherapy for stem cell mobilization, and again at 1000 mg/m2, 7 days later. Pts then received additional R at 1000 mg/m2 on days +1 and +8 after ASCT, as previously described. Pts were staged with CT, PET (whenever indicated) scans, bone marrow biopsy, and colonoscopy (if history of GI involvement) every 3 months for the first year, every 6 months for 5 years, then yearly thereafter. Results: a.SOX11: Formalin-fixed, paraffin-embedded tissue biopsy sections were assessed by immunohistochemistry (IHC) using anti-Sox-11 rabbit polyclonal antibody (Abcam, Cambridge, MA; 1:1500). For IHC controls we used a tissue microarray including 13 cases of MCL in addition to one complete section of MCL serving as positive controls, and sections from two cases of small lymphocytic lymphoma involving lymph node serving as negative controls. The 11 cases consisted of five GI biopsies, three lymph node biopsies, two bone marrows and one testis. 10/11 showed positive staining for SOX11. The case with negative staining, a GI biopsy, had scattered positive cells. b.Clinical outcome : Following transplantation, CR/CRu was achieved in 100% pts. With a median follow-up of 37 months (range, 6–145), 10 pts experienced recurrent disease. All progressions occurred within 3 years, with a clear plateau emerging subsequently (Figure). The projected lymphoma-free-survival at 10-year, was 65% (95%CI, 44–80). A tendency for a higher risk of relapse was observed in R-hyper-CVAD resistant pts (Group B) pts [4/10 pts (40%) vs 6/30 (20%) in Group A; HR 2.5 (95%CI, 0.7–9.2), p=0.2)], and in pts with ki-67 ≥30% [HR 2.2 (95%CI, 0.4–11), p=0.3). MIPI, blastic histology, age (> 60 years), disease status at transplant (CR/PR) and conditioning were not found to be of prognostic value in our study. 2 pts (5%) developed myelodysplasia, one of which was concurrent with progression. [Display omitted] Conclusions:ASCT with high-dose rituximab has the potential to cure a proportion of pts with MCL after response to induction chemotherapy. Our results are favorable despite the inclusion of pts who were resistant to R-hyper-CVAD. Randomized studies comparing this strategy to conventional chemo-immunotherapy are warranted. The prognostic significance of Ki-67 level needs to be assessed in a larger cohort of patients. Disclosures:No relevant conflicts of interest to declare.

Optimal timing of G-CSF administration for effective autologous stem cell collection

The best time of G-CSF administration for PBPC collection remains to be defined. We aimed to identify optimal G-CSF administration timing for efficient autologous stem cell collection. A total of 262 lymphoma or multiple myeloma patients, who underwent PBPC collection from January 2000 to March 2008, were included. PBPCs were mobilized with chemotherapy followed by lenograstim at 10 μg/kg/day. Patients received lenograstim at 2000 hours, about half a day before leukapheresis (PM group) before November 2004, and at 0600 hours, 3 h before apheresis (AM group) subsequently. In the AM group, the median number of total collected CD34+ cells/kg was greater over a shorter duration of apheresis, and the median number of collected CD34+ cells/kg at first leukapheresis was larger. Stem cell collection efficacy (ratio of total collected CD34+ cells/kg per number of leukapheresis procedures) was higher, and proportion of patients who yielded an optimum harvest was larger. The statistically significant between-group difference was observed only in patients with high-dose CY chemotherapy for stem cell mobilization in subgroup analysis. The present study showed that G-CSF injection 3 h before apheresis improved the efficacy of autologous stem cell collection.

Superior Survival in Non-Hodgkin Lymphoma Following Autologous Stem Cell Transplantation with Intravenous Busulfan, Cyclophosphamide, and Etoposide.

Preparative regimens for autologous stem cell transplantation (ASCT) are distinguished mainly by their toxicities, not differences in their antitumor efficacy. Erratic gastrointestinal absorption confers a narrow therapeutic range for oral busulfan-based regimens, whereas the bioavailability and pharmacokinetic (PK) profile of intravenous (IV) busulfan are highly predictable. In a pilot study, we observed better relapse-free survival among lymphoma patients over 50 years old who underwent ASCT after high-dose busulfan, cyclophosphamide, and etoposide (BuCyVP) with IV busulfan in place of oral busulfan. This analysis describes outcomes of ASCT for 604 adult patients with non-Hodgkin lymphoma (NHL) who received IV busulfan (N=136) or oral busulfan (N=468) as part of conditioning with BuCyVP from 1996 through 2007 at the Cleveland Clinic. Oral busulfan was used in the preparative regimen through 10/2004 in patients older than 50 years and through 5/2006 in patients age 50 years or younger; after these dates, IV busulfan was used. The regimen consisted of busulfan (1 mg/kg PO or 0.8 mg/kg IV) Q6 hours x 14 doses; etoposide 60 mg/kg IV over 36 hours; and cyclophosphamide 60 mg/kg IV daily for 2 consecutive days. Busulfan levels were not measured. Patients who received IV rather than oral busulfan were older (median 58 vs. 51 years), had less advanced stage, had diffuse large B-cell NHL (DLBCL) or high-risk IPI scores less frequently, were more heavily pretreated (3 or more regimens in 40% vs. 25%), and received chemotherapy for stem cell mobilization more frequently. Prior radiotherapy, disease status at transplant, and CD34+ cell dose were similar between groups. Mean scores using the Oral Mucositis Assessment Scale (OMAS) during ASCT indicated more severe mucositis with oral busulfan than with IV busulfan (0.90 versus 0.54, P<0.001). Although the times to neutrophil and platelet engraftment were equivalent, median length of stay was 1 day shorter for IV versus oral busulfan (P<0.001). Median follow-up was 69 months versus 15 months for oral and IV busulfan recipients, respectively. Overall survival (OS) and relapse-free survival (RFS) were superior in patients receiving IV versus oral busulfan (median OS not observed versus 72 months, P=0.03; median RFS not observed compared with 31 months, P=0.005). Nonrelapse causes accounted for 65/225 deaths (29%) among oral busulfan recipients and 3/24 deaths (12.5%) among IV busulfan recipients. In multivariable Cox proportional hazards analysis using stepwise selection, IV versus oral busulfan was associated with superior OS (P=0.002) and RFS (P=0.001), and a lower risk of relapse (P=0.013). Other factors significantly associated with improved OS and RFS in multivariable analysis included younger age (OS: P<0.001; RFS: P=0.004), B-cell versus T-cell NHL histology (OS and RFS: P<0.001), less extensive prior therapy (OS and RFS: P<0.001), and chemotherapy-sensitive disease before ASCT (OS and RFS: P<0.001). Relapse was also associated with NHL subtype (T-cell versus others, P<0.001), extent of prior therapy (P<0.001), and disease status (P<0.001). In summary, IV busulfan in conditioning with BuCyVP for ASCT is associated with superior non-relapse mortality, RFS, and OS compared with oral busulfan in patients with NHL. These findings suggest that IV busulfan is not only less toxic but also a more effective anticancer agent than oral busulfan. Alternate dosing schedules and PK-directed dosing may enable the activity of IV busulfan to be optimized further in ASCT for NHL. [Display omitted]

Zevalin®/BEAM/Rituximab vs BEAM/Rituximab and Autologous Stem Cell Transplantation (ASCT) for Relapsed Chemosensitive Diffuse Large B-Cell Lymphoma (DLBCL): Impact of the IPI and PET Status.

Background: The addition of rituximab (R) has improved results for pts with relapsed DLBCL who undergo high-dose chemotherapy followed by ASCT (Khouri, JCO, 2005). Recently, the incorporation of radio-labeled antibodies such as Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) to conditioning regimens has been evaluated. Herein, we compare the outcome in pts treated with these 2 regimens.Methods: Pts with relapsed chemosensitive DLBCL were treated on 2 consecutive trials. Between 1999 and 2003, 53 pts were enrolled on a protocol with BEAM combined with R at 1000 mg/m2 and on days +1 and +8 after ASCT (R-BEAM). Between 2004 and 2006, 25 pts were entered onto a trial of Zevalin given at the fixed dose of 0.4 mCi/Kg on day -14 followed by BEAM (days −7 to −1) with R on days +1 and +8 after ASCT (Z-BEAM). Both groups received R during stem cell collection at a dose of 375 mg/m2 the day before chemotherapy for stem cell mobilization and at 1000 mg/m2 7 days later. There was no statistical difference in age, sex distribution, # of prior therapies between the 2 groups. LDH, PET and remission status at transplant were comparable. However, serum b2- microglobulin level was higher in R-BEAM pts [median 2.2 vs 1.9, (p=.02)] and they were also more likely to have an IPI ≥ 1: 39% vs 8% (p=0.005).Results: Median follow-up: 18 mos (range, 6–35) in Z-BEAM and 52 mos (range, 21–74) for R-BEAM. Both groups were staged with CT, PET scan and marrow biopsies, every 3 mos for a year, and then every 6 mos. OS and DFS @ 2 yrs were 92% (95% CI, 72–98) and 84% (95% CI, 62–93) for Z-BEAM vs. 83% (95%CI, 70–91) and 72% (95% CI, 57–82) for R-BEAM (P = 0.5 for both OS/DFS). Within the R-BEAM group, PET status and IPI at transplant were important prognostic factors for OS {91% vs 50% for PET (−) and (+), P = 0.004; 94% vs 67% for IPI 0 vs. ≥1, P = 0.02} and DFS. DFS of pts with IPI 0 were 86% vs 81% for Z-BEAM and R-BEAM, respectively (P = 0.9). A comparison for high IPI pts could not be done due to the small number of such pts in the Z-BEAM group. DFS for pts who were PET (+) were 75% vs 44% within the Z-BEAM and R-BEAM groups, respectively: a difference that did not reach significance due to the small number of pts (4 vs 10). Treatment-related mortality was comparable with only one early death within the Z-BEAM group due to sepsis. Results suggest a faster WBC recovery with Zevalin {ANC > 500, day +9 vs. day +11 (p<0.001)}. However, results may be confounded by the use of different cytokines. Platelet engraftment was similar in both groups.Conclusions: Fixed dose Zevalin of 0.4 mCi/kg can be added to BEAM without increasing toxicity. Z-BEAM and R-BEAM have comparable results in relapsed chemosensitive DLBCL pts with IPI 0 and PET (−) at transplant. Pts with IPI ≥ 1 and PET (+) have suboptimal results with R-BEAM. Randomized trials are needed to address whether the addition of Zevalin for these pts may improve their outcome.

The Combination of 2-CDA and Rituximab in Patients with Chronic Lymphocytic Leukemia (CLL): A Prospective Multicenter Phase II Trial (SAKK 34/02).

Introduction: This trial aimed to determine the efficacy and toxicity of an induction immunochemotherapy consisting of rituximab and cladribine (2-chlorodeoxyadenosine, 2-CDA) in patients (pts) suffering from chronic lymphocytic leukemia (CLL).Methods: Inclusion criteria were CLL at first diagnosis or after one treatment with alkylating agents. The regimen consisted of four remission induction cycles. In cycle 1, 2-CDA (0.1 mg/kg/day) was administered for 5 days. In cycles 2-4, Rituximab (375 mg/m^2) was given on day 1 followed by 2-CDA (0.1 mg/kg body weight), in intervals of 28 days. Responding pts (complete remission (CR), very good partial remission (VGPR) or nodular partial remission (NPR)) underwent stem cell mobilization chemotherapy with Cyclophosphamide (4g/m^2 on day 2) G-CSF (10 microgram/kg s.c. daily, from day 4 on), and Rituximab (375 mg/m^2) on day 1 and 8 as in vivo purging. If no CR, VGPR or NPR was achieved, up to 4 cycles CHOP were administered. Primary endpoint was CR, secondary endpoints were VGPR, NPR and toxicity after induction and feasibility of stem cell mobilization. For response evaluation, staging procedures included clinical examination as well as bone marrow biopsies and CT-scans. A total of 41 pts was planned using Simon's two-stage design with 5% significance and 80% power for the null hypothesis of CR rate < 25% and the alternative hypothesis of CR rate > 45%.Results: 42 pts were included, median age 53.8 y (range 38 – 65), WHO performance status 0 in 33 pts and 1 in 9 pts, stage Binet B in 20 pts, Binet C in 8 pts and progressive A in 14 pts. 2 pts were not evaluable for response. 9 pts reached CR (22.5%, 95% CI: 11–38%). Overall response rate including 15 VGPR and 2 NPR was 65% (CI: 48–79%). Of the 14 non-responders, 8 underwent CHOP treatment of which 2 achieved VGPR. 20 patients underwent mobilization and 8 pts refused further protocol treatment. 14 pts had leucapheresis. Stem cell harvest was feasible in 7 pts, all with ≥ 2×10^6 cells/kg. Fever and infection were reported respectively in 13 and 9 pts. Infusion related adverse events of Rituximab were moderate and occurred mainly after the first infusion. 42 of 158 cycles (27%) were associated with grade 3 or 4 neutropenia and 6 of 158 cycles (4%) with grade 3 thrombocytopenia.Conclusions: Although the expected CR rate was not achieved, a combination of Rituximab and 2-CDA is an effective and well tolerated treatment.

The Use of Intravenous Compared with Oral Busulfan in High-Dose Chemotherapy and Autologous Stem Cell Transplantation (ASCT) for Lymphoma Is Associated with Improved Relapse-Free Survival.

The efficacy of high-dose chemotherapy and ASCT for lymphomas is generally believed to be independent of the preparative regimen used, although toxicities may vary. Delayed toxicities after ASCT led us to investigate IV busulfan in older patients as a substitute for oral busulfan in a preparative regimen of busulfan/cyclophosphamide/etoposide (BuCyVP), based on data suggesting lower treatment-related mortality after ASCT with the IV formulation. We then queried whether other outcomes of ASCT for lymphomas were improved by substituting IV busulfan for oral busulfan. We retrospectively analyzed the outcomes of 308 patients over age 50 years who underwent ASCT for NHL (93%) or HL (7%) at the Cleveland Clinic from 1996 through 2/2006. Oral BuCyVP (“PO Bu”) was used in 261 patients and IV BuCyVP (“IV Bu”, 0.8 mg/kg IV x 14 doses given without monitoring or adjustment for serum Bu levels) in 47 patients. Differences in baseline characteristics were that the IV Bu group was more heterogeneous in the number of prior chemotherapy regimens (P=0.013), more often received chemotherapy for stem cell mobilization (P=0.026), had fewer NHL patients with a high-intermediate or high IPI score (P<0.001), and had fewer patients with stage III or IV disease (P=0.046). Follow up from ASCT was significantly longer in the PO Bu group (median 45.7 vs. 8.8 months). CD34+ cell doses and hematopoietic recovery were similar between groups.Median overall survival was 43.6 months after ASCT with PO Bu but was not reached for the IV Bu group. Kaplan-Meier analysis demonstrated the unanticipated finding that IV Bu was associated with a lower rate of relapse (P=0.013), superior relapse-free survival (P=0.008), and a marginal improvement in overall survival (P=0.06). [Display omitted] Univariate Cox models identified the route of busulfan administration and disease status at ASCT as significant predictors of relapse. Age at transplant, the number of prior regimens, and LDH at transplant were significant predictors of mortality. Only the route of busulfan administration significantly predicted RFS in univariate analysis. In a multivariable model, the route of busulfan administration was the strongest predictor of RFS (P=0.043). Age was also predictive of RFS (P=0.047). These preliminary results suggest that replacing PO Bu with IV Bu is associated with a reduced relapse rate and improved RFS following ASCT for lymphoma. In contrast to other reports, we observed these improvements without targeting Bu dosage according to serum levels. Further study is necessary to confirm these findings and to ascertain whether IV Bu will favorably influence overall survival in this setting.

Infections during mobilizing chemotherapy and following autologous stem cell transplantation.

Autologous peripheral blood stem cells (PBSC), for transplantation following high-dose chemotherapy, are collected using regimens containing cytokines with or without chemotherapy. The added period of neutropenia prior to stem cell transplantation (SCT) in patients receiving chemotherapy mobilization may increase the risk of infections following transplantation. We studied the incidence of culture-positive infections in 107 consecutive patients who were divided into three groups, according to whether they experienced extended neutropenia during chemotherapy for stem cell mobilization as well as post autotransplant. All the patients received antibiotic prophylaxis and hematopoietic growth factors during neutropenia. The total duration of pre-transplant neutropenia differed among the three mobilization schemes (growth factors alone; one cycle; or two cycles of chemotherapy plus growth factor for mobilization) at 0, 6 and 18 days, respectively (median). However the post-autograft time to myeloid engraftment was similar at 10 days (median). The incidence of culture-proven infections in all three groups was similar. Using fluconazole for yeast prophylaxis, 40% patients developed gastrointestinal colonization with yeast, and the majority of speciated isolates were Candida glabrata. Bacteremia developed in 22% and 9% of patients with S. epidermidis and Gram-negative organisms, respectively, while 11% developed C. difficile-associated diarrhea. In conclusion, treatment using none, one or two cycles of mobilizing chemotherapy pre-transplant does not influence the overall incidence of infections among autologous SCT recipients. However, although post-transplant neutropenia is brief, infections remain a significant cause of morbidity.

Varicella zoster virus infection associated with high-dose chemotherapy and autologous stem-cell rescue.

A retrospective evaluation of 215 consecutive recipients of high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) was conducted to ascertain the incidence, temporal course, and outcome of varicella zoster virus (VZV) infection. Herpes zoster was identified in 40 individuals at a median of 69 days following ASCR. Six of these cases occurred at a median of 33 days prior to ASCR but following the initiation of high doses of stem cell mobilization chemotherapy. Twenty-five percent of patients demonstrated cutaneous or systemic dissemination and 32.5% required medical intervention for post-herpetic neuralgia. All except two individuals received antiviral chemotherapy. One patient with active VZV infection died of multiorgan failure 39 days after ASCR. Multivariate analysis of risk factors disclosed the significance of prophylactic acyclovir use in Herpes simplex virus seropositive individuals in reducing the risk of VZV infection. Moreover, the use of busulfan, thiotepa and carboplatin as the conditioning chemotherapy regimen was associated with an increased risk of subsequent VZV infection. The incidence of VZV reactivation after HDC and ASCR is similar to that observed following bone marrow transplantation but has an earlier onset. This may be related to an earlier induction of immunosuppression by stem cell mobilization chemotherapy administered prior to ASCR. We demonstrated a marked reduction in the proliferative and synthetic capacities of peripheral blood mononuclear cells obtained prior to and following stem cell mobilizing chemotherapy. Moreover, greater than 80% of VZV infections occurred within 6 months following ASCR and late cases were seldom observed compared to allogeneic and autologous bone marrow transplantation. The role of antiviral chemoprophylaxis during the period of maximum immunocompromise needs to be studied further in the HDC-ASCR setting.