Tandem Peripheral Blood Stem Cell Research Articles

Monitoring of Post-Transplant Hematopoiesis in Patients Receiving High-Dose Yttrium-90-Ibritumomab Tiuxetan (Zevalin®) with Autograft: Lack of Detection of Remarkable Abnormalities.

Introduction: High-dose (hd) Zevalin® radioimmunotherapy (RIT) followed by tandem peripheral blood stem cell (PBSC) reinfusion is a well tolerated myeloablative regimen with wide applicability for the treatment of NHL (Devizzi L et al, J Clin Oncol, in press). The risk of long-term hematopoietic damage and therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) due to high radiation doses to the bone marrow (BM) is a matter of concern. The present study aimed to investigate BM hematopoietic abnormalities after hd-Zevalin®.Patients and Methods: From July 2004 through December 2007, 51 consecutive NHL patients (M/F=30/21; median age 64 yrs, range 26–76 yrs) who received hd-Zevalin® (1.2 mCi/kg) as myeloablative consolidation following sequential hd-chemotherapy were monitored after transplantation for BM progenitor cell frequency, telomere length (TL) and cytogenetic abnormalities. Disease histology included diffuse large B cell (n=21), follicular (n=19), mantle cell (n=8), marginal zone (n=2), and small lymphocytic (n=1) lymphomas. At study entry, 35 patients had relapsed or refractory disease, whereas 16 patients were chemotherapy-naive with high-risk prognostic index. Following hd-RIT, 33/51 patients were reinfused with PBSC collected after hd-cytarabine. BM and peripheral blood (PB) mononuclear cells (MNC), collected prior to Zevalin® and at 6-month intervals thereafter, were analyzed for (i) frequency of BM erythroid BFU-E, myeloid CFU-GM, and multilineage CFU-mix, (ii) TL, (iii) cytogenetic abnormalities.Results: With a median follow-up of 25 months (range, 8–50) from autograft, a total of 196 samples have been analyzed: 51 at baseline, 39 at 6 months, 42 at 12 months and 27, 27 and 10 at 18, 24 and 36 months after RIT, respectively. As compared to pre-transplant values, a significant reduction in BM CFCs was detected 6 months after Zevalin® (median incidence per 5 x 104 MNCs were as follows, BFU-E: 45 vs 26, P≤0.04; CFU-GM: 61 vs 34, P≤0.0005; CFU-mix: 0.8 vs 0.5, P≤0.2). CFCs recovered to pre-transplant values 12 months after Zevalin®, and showed sustained growth values at subsequent time-points. No difference in progenitor cells was observed by comparing Zevalin® patients with those conditioned with conventional chemotherapy. Telomere was steadily assessed in 27 patients. Similar values (p=NS) of TL were obtained on pre-transplant MNCs (median: 5,893 bp, range 4,107–8,353) and MNCs collected at 6–12 months post-transplant (median: 5,829 bp, range 3,133–8,037). BM cytogenetic analysis has been serially performed in 51 patients. To date, abnormalities have been detected in 2 cases, including one deletion of chromosome 7 and one inversion of chromosome 16 [inv(16)]. Interestingly, inv(16) was retrospectively detected in the leukapheresis collected before RIT, thus ruling out any causative role of Zevalin®.Conclusion: In this cohort of elderly and heavily pretreated patients receiving hd-Zevalin®, hematopoietic function evaluated by progenitor cell growth and TL seems comparable to that of patients receiving conventional myeloablative chemotherapy. No increase in cytogenetic abnormalities was detected up to 36 months post-transplant. A careful monitoring is still ongoing in order to verify at long-term whether hd-Zevalin® might increase the risk of t-MDS/AML.

Late effects in survivors of tandem peripheral blood stem cell transplant for high-risk neuroblastoma.

Increasing numbers of children with advanced neuroblastoma are achieving cure. We describe the clinical late effects specific to survivors of stage IV neuroblastoma all similarly treated using tandem autologous peripheral blood stem cell rescue with TBI. The medical records of 35 neuroblastoma patients treated at CHOP between 1997 and 2001 were examined. Eighteen of the 35 patients died of progressive disease, and 4 were lost to follow-up. Thirteen patients continue to follow-up in our Multidisciplinary Cancer Survivorship Clinic where they are evaluated and monitored by a consistent group of subspecialists that evaluate long-term sequelae. Data on treatment exposures including TBI and treatment related sequelae identified by clinician assessment and/or diagnostic testing were collected. Results indicate late effects were present in all 13 subjects, 12 of whom suffered from multiple negative sequelae, including issues with growth hormone deficiency, dental problems, osteochondromas and hearing deficiencies, among others, most at higher rates than reported previously. The findings in this small cohort indicate the need for future prospective studies of this intensive pediatric cancer treatment, and underscore the importance of medical intervention and long-term monitoring of these at-risk subjects to increase overall quality-of-life.

184: Phase I Study of Bortezomib, (BTZ) followed by High-Dose Melphalan, (HD Mel) and BTZ as Conditioning Regimen for Tandem Peripheral Blood Stem Cell Transplants (TanPSCT) in Patients with Primary Refractory Multiple Myeloma (MM) and Plasma Cell Leukemia (PCL)

184: Phase I Study of Bortezomib, (BTZ) followed by High-Dose Melphalan, (HD Mel) and BTZ as Conditioning Regimen for Tandem Peripheral Blood Stem Cell Transplants (TanPSCT) in Patients with Primary Refractory Multiple Myeloma (MM) and Plasma Cell Leukemia (PCL)

Phase I Study of Bortezomib, (BTZ) Followed by High-Dose Melphalan, (HD Mel) and BTZ as Conditioning Regimen for Tandem Peripheral Blood Stem Cell Transplants (TanPSCT) in Patients with Primary Refractory Multiple Myeloma (MM) and Plasma Cell Leukemia (PCL).

Background: Approximately 25% of patients with newly diagnosed (MM) fail to respond and progress while receiving conventional induction. As a result, these patients have primary refractory disease. Even though these patients still benefit from HD chemotherapy, their PFS ranges from 4–8 months, while OS is approximately 12 months. PCL accounts for approx. 2% of newly diagnosed MM patients and represents the most aggressive form of disase. These patients often do not respond to standard systemic cytotoxic therapies and their median survival is less than 12 months. Therefore, novel treatment approaches are paramount for patients with primary refractory MM and PCL. The proteasome inhibitor BTZ has been shown to sensitize myeloma cells to melphalan both in vitro and in vivo, but the mechanism is not well understood. In this study we examine the effects of BTZ, followed by BTZ and HDMel as conditioning regimen for TanPSCT in this poor-risk group.Methods: Patients with primary refractory MM or PCL received 2 cycles of BTZ at 1.3 mg/m2. followed by HD Mel (200 mg/m2) and one dose of BTZ at 0.7 mg/m2, 1.0 mg/m2 or 1.3 mg/m2, as a conditioning regimen prior to TanPSCT. The dose of BTZ was given immediately after the last dose of HD Mel. Bone marrow(BM) samples were collected at baseline, on day 4 and after 2 cycles of BTZ, and at 3 months after TanPSCT, for GEP and Fanconi anemia(FA) pathway genes assessment.Results: To date, 17 patients have been enrolled and treated, and 11 patients are evaluable for response. Median age is 59 years (46–70) with the following myeloma distribution: 55% IgA and 45% IgG. FISH analysis showed the following: del 13q (44%), t (4; 14) (11%), t (11; 14) (11%), trisomy 11 (11%), and polyploid (11%); standard karyotype was normal in 88% of patients and complex karyotype in 12%. Median time to WBC engraftment (days) was 13 and 12 after the first and second transplant, respectively. Median time to plt engraftment (days) was 20 and 17, after the first and second transplant, respectively. There were no dose limiting toxicities. Observed grade 3 toxicities were related to the conditioning regimen and similar to those observed with HDMel alone. One patient developed diffuse alveolar hemorrhage after the first cycle of BTZ, which resolved, but was removed from study. After 2 cycles of BTZ, 45% of patients achieved PR, and 55% had stable disease. Overall response rate at 3 months from the second transplant increased to 90%(CR=36%,VGPR=27% andPR=27%). Only 1 patient developed progressive disease after the first transplant. Evaluations of BM samples by GEP and FA pathway gene expression are underway.Conclusions: Single agent BTZ induced responses in 45% and the combination of HD Mel and BTZ as conditioning regimen for TanPSCT was well tolerated and improved response rates to 90%. These early results suggest that this regimen is very active in this poor-risk group. Evaluation of collected BM samples for GEP and FA pathway genes may provide important insight into the mechanisms associated with the observed synergy between BTZ and HD Mel. A Phase II study is underway.

A randomized trial of home-based exercise for patients receiving aggressive treatment and epoetin alfa for multiple myeloma: Hemoglobin (Hb), transfusion, fatigue and performance as outcomes

8026 Background: Over 60% of patients with multiple myeloma (MM) are anemic (Hb < 12 g/dL) at diagnosis. Nearly all become anemic during aggressive treatment for MM and many require red blood cell (RBC) transfusions. Anemia can contribute to fatigue, the most common and often the most distressing symptom for patients with cancer. Methods: A randomized trial with repeated measures compared the effects on fatigue and performance of a home-based exercise program that combines aerobic and strength resistance training with a usual care/control condition. Measurements were the Profile of Mood States (POMS) fatigue scale, Functional Assessment of Cancer Therapy - Fatigue (FACT-F) and 6-minute walk test. Patients were newly diagnosed with MM and were enrolled in an aggressive treatment protocol that included tandem peripheral blood stem cell transplants. All patients in the study received epoetin alfa according to an algorithm that allowed increases in Hb up to 15 g/dL before dose reductions or delays. Planned enrollment is 160. Results: The table below shows data from 82 patients with measurements at baseline just before induction chemotherapy and just before stem cell mobilization. Trends toward less fatigue and better performance are seen in the exercise group compared to the control group. Conclusions: These preliminary findings suggest exercise therapy during aggressive treatment for MM benefits patients by decreasing their fatigue and improving their performance status. No significant financial relationships to disclose.

A randomized trial of home-based exercise for patients receiving aggressive treatment and epoetin alfa for multiple myeloma: Hemoglobin (Hb), transfusion, fatigue and performance as outcomes

8026 Background: Over 60% of patients with multiple myeloma (MM) are anemic (Hb < 12 g/dL) at diagnosis. Nearly all become anemic during aggressive treatment for MM and many require red blood cell (RBC) transfusions. Anemia can contribute to fatigue, the most common and often the most distressing symptom for patients with cancer. Methods: A randomized trial with repeated measures compared the effects on fatigue and performance of a home-based exercise program that combines aerobic and strength resistance training with a usual care/control condition. Measurements were the Profile of Mood States (POMS) fatigue scale, Functional Assessment of Cancer Therapy - Fatigue (FACT-F) and 6-minute walk test. Patients were newly diagnosed with MM and were enrolled in an aggressive treatment protocol that included tandem peripheral blood stem cell transplants. All patients in the study received epoetin alfa according to an algorithm that allowed increases in Hb up to 15 g/dL before dose reductions or delays. Planned enrollment is 160. Results: The table below shows data from 82 patients with measurements at baseline just before induction chemotherapy and just before stem cell mobilization. Trends toward less fatigue and better performance are seen in the exercise group compared to the control group. Conclusions: These preliminary findings suggest exercise therapy during aggressive treatment for MM benefits patients by decreasing their fatigue and improving their performance status. No significant financial relationships to disclose.