Autologous Hematopoietic Progenitor Cell Transplantation Research Articles

Factors that predict successful remobilization after autologous hematopoietic progenitor cell transplant (aHCT) for multiple myeloma.

8610 Background: aHCT is a proven therapeutic modality in treating relapsed multiple myeloma (MM). However, previously transplanted patients may have no hematopoietic progenitor cells (HPC) left in storage. Methods: Collection of HPC after aHCT was studied in 221 MM patients who underwent 333 mobilization attempts between 10/2000 and 06/2012. Results: The median number of CD34+ collected was 4.7 ×106/kg, with 74% of collections yielding at least 2.5×106/kg. Mobilization with chemotherapy and G-CSF was most efficient, yielding a median of 6.84×106/kg (p<0.001). Growth factor-only mobilization was least effective, with a median of 3.01×106/kg (p<0.001). The addition of plerixafor yielded a significant increase if there was a previous “poor” (<2.5×106/kg) collection (1.83 vs. 3.43×106/kg, p<0.001). In univariate statistical analysis female sex (p=0.048), platelets (PLT) ≤100×106/L (p<0.001), hemoglobin ≤11g/dL (p=0.032), and albumin ≤3.5 g/dL (p=0.003) prior to mobilization correlated with a “poor” collection. In multivariate analysis only PLT ≤100×106/L was significant (p<0.001). Of the 221 patients collected, 154 underwent subsequent aHCT. Infusion of HPC procured after previous aHCT did not yield a difference in treatment-related mortality (p=0.766). Use of only cells collected after aHCT was related to a delayed platelet engraftment ≥50×106/L (p<0.001). Conclusions: Remobilization and collection of an adequate number of HPC after previous aHCT is feasible. PLT ≤100×106/L suggest the need for plerixafor for a successful collection. Infusion of the graft procured is safe and effective, but use of only cells collected after aHCT is associated with delayed platelet engraftment >50×106/L.

Addressing the questions of tomorrow: melphalan and new combinations as conditioning regimens before autologous hematopoietic progenitor cell transplantation in multiple myeloma

Introduction: The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (auto-HPCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. Administration of high-dose melphalan (HDM) is considered the standard conditioning regimen. Nevertheless, several attempts have recently been made to improve the conditioning phase of the HDC procedure.Areas covered: We reviewed all the reported experiences and illustrated current knowledge in the field of conditioning regimens.Expert opinion: For fit MM patients, HDC followed by auto-HPCT remains the standard of care. The available data confirm that melphalan (MEL) 200 mg/m2 should continue to be considered the gold standard conditioning regimen, with dose reduction based on age and renal function. Targeting exposure to MEL by using area under the curve is a particularly appealing approach that could be explored to maximize efficacy and minimize toxicity of this drug. Other strategies are currently being evaluated in different trials, and the most interesting areas of research involve the incorporation of newer agents like bortezomib (BOR) into conditioning regimens. Moreover, intravenous busulfan has become available and this formulation may reduce toxicity and result in greater efficacy in association with MEL-based conditioning.

Multi-Center Phase I Study of Th1/Tc1 Immunotherapy Following Autologous Hematopoietic Progenitor Cell Transplantation in Reccurrent or High Risk Plasma Cell Myeloma

Multi-Center Phase I Study of Th1/Tc1 Immunotherapy Following Autologous Hematopoietic Progenitor Cell Transplantation in Reccurrent or High Risk Plasma Cell Myeloma

Intravenous Compared to Oral Busulfan with Cyclophosphamide for Autologous Hematopoietic Progenitor Cell Transplant Conditioning for Plasma Cell Myeloma

s / Biol Blood Marrow Transplant 19 (2013) S178eS193 S190 (calculated from diagnosis) was 131 months and the fiveyear overall survival rate was 55.5%. Conclusions: In our experience, ASCT was associated with excellent disease control and outcomes in patients with relapsed refractory LPHL.

A Novel Hematopoietic Progenitor Cell (HPC) Mobilization Regimen, Utilizing Bortezomib and Filgrastim (G-CSF), for Patients Undergoing Autologous HPC Transplant (AHPCT) for Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

A Novel Hematopoietic Progenitor Cell (HPC) Mobilization Regimen, Utilizing Bortezomib and Filgrastim (G-CSF), for Patients Undergoing Autologous HPC Transplant (AHPCT) for Multiple Myeloma (MM) and Non-Hodgkin's Lymphoma (NHL)

Tandem Autologous Hematopoietic Progenitor Cell Transplantation (AHPCT) for High-Risk Hodgkin Lymphoma: Mature Results of a Prospective Trial

Abstract 1990▪▪This icon denotes a clinically relevant abstractThe efficacy of high-dose chemotherapy (HDC) and AHPCT is inferior for Hodgkin lymphoma patients (pts) with high-risk features, commonly defined as primary induction failure (PIF) or early relapse (within 1 year of achieving remission). Phase II studies have suggested that tandem courses of HDC with AHPCT may improve transplant outcomes. We therefore evaluated this approach in a single-center, prospective, phase II study. The primary endpoint of the trial was relapse-free survival (RFS). The intention-to-treat (ITT) analysis included 42 subjects with PIF or early relapse (within 1 year) who signed consent, of whom 37 underwent both transplants in 2002–2010 (3 were denied insurance coverage for tandem AHPCT, 1 had inadequate HPC harvest, and 1 withdrew). These subjects were compared retrospectively with 96 control pts who met eligibility criteria for the trial and underwent a single AHPCT from 1995–2009. HPC mobilization was with etoposide/filgrastim in all tandem AHPCT subjects, and in 55% of controls. Tandem pts received melphalan 150 mg/m2 with AHPCT. After a median of 52 days, tandem pts then received CBV (N=30) or busulfan, etoposide, and cyclophosphamide (BuCyVP; N=7, due to carmustine shortage) with AHPCT. Controls received BuCyVP (N=95) or CBV (N=1) with AHPCT. There were no clinically significant baseline differences between the tandem and control groups.With a median 54 months follow-up at the time of analysis among tandem AHPCT survivors, 23 tandem pts and 47 controls were alive at the time of analysis. Causes of death among tandem AHPCT recipients included relapse (N=13), pulmonary (N=1), secondary malignancy (N=3), other (N=2). For controls, causes of death included relapse (N=37), pulmonary (N=2), secondary malignancy (N=2), other (N=8). Among tandem pts who received both transplants, 100-day mortality did not occur; there were 7 deaths within 100 days post AHPCT among controls (P=0.09). Median RFS was 15.5 months for tandem pts and 26.3 months for controls (P=0.28). Median overall survival (OS) was 54.9 months for tandem pts vs. 73.1 months for controls (P=0.76). [Display omitted] In multivariable analysis, factors associated with survival included race (non-Caucasian vs. Caucasian, HR 2.68, 95% CI 1.30–5.54, P=0.008), extent of prior chemotherapy (per 1 regimen increase, HR 2.54, 95% CI 1.71–3.77, P<0.001), and disease bulk (>10 cm vs. < 10 cm, HR 2.76, 95% CI 1.57–4.84, P<0.001). For RFS, prognostic factors included extent of prior chemotherapy (HR 2.15, 95% CI 1.47–3.13, P<0.001), disease bulk (HR 1.89, 95% CI 1.14–3.15, P=0.014), and disease status at transplant (relapsed/refractory vs. CR/PR, HR 1.91, 95% CI 1.14–3.20, P=0.014).In conclusion, tandem AHPCT provides no demonstrable advantage over a single course of HDC with AHPCT in our analysis. More effective treatments are needed for pts with high-risk Hodgkin lymphoma, particularly ethnic minorities or those with bulky disease at transplant. Transplant outcomes suffered with additional lines of therapy before AHPCT, as shown in other published studies; thus, AHPCT should be prioritized over other interventions whenever feasible, at the time of induction failure or first relapse. Disclosures:No relevant conflicts of interest to declare.

The use of adjusted ideal body weight for overweight patients undergoing HPC mobilisation for autologous transplantation

Generally, patients' actual body weight (ABW) is used to calculate the number of CD34⁺ cells to be harvested for autologous haematopoietic progenitor cell (HPC) transplantation. In our institution, 'overweight' patients weighing at least 25% more than their ideal body weight (IBW) have their adjusted ideal body weight (AdjIBW) used for determination of blood volume to be processed to achieve a minimum target of CD34⁺ cells per kilogram, as well as CD34⁺ cell dosage calculation at transplant. AdjIBW is calculated as follows: AdjIBW = IBW + 0.25 × (actual weight - IBW). We have used AdjIBW for 65/153 patients who have had autologous HPC harvests, with a median AdjIBW of 69 kg (range, 50-110 kg). Median actual weight was 90 kg (range, 62-175 kg). Median volume of peripheral blood processed to achieve a minimum 2 × 10⁶ CD34⁺ cells/kg for these patients was 13.2 L (range, 5-35 L), and the median CD34⁺ cells × 10⁶/kg collected for AdjIBW was 6.3 (range, 1.7-33). For normal-weight patients (n = 88; median ABW, 75 kg; range, 49-98 kg), the corresponding median apheresis volume was 16 L (range, 7-24 L), and median CD34⁺ cells × 10⁶/kg harvested was 4.5 (range, 1.4-15.9). In total, 35 in a total transplant cohort of 82 patients had AdjIBW used to determine CD34⁺ cell dose at time of transplant, with a median of 4.5 × 10⁶/kg, (if their ABW was used in the calculation; 3.1 × 10⁶/kg), compared to median dose of 3.2 × 10⁶/kg ABW for the normal-weight patient cohort. All patients engrafted with no significant difference between median times to neutrophil and platelet engraftment for the overweight (13 and 15 days, respectively) compared with normal-weight (12 and 14 days, respectively) patient cohorts. We conclude that the use of AdjIBW is a useful tool for successful harvest and subsequent transplant for overweight patients, with no adverse effect on engraftment times.

A prospective clinical trial evaluating the safety and efficacy of the combination of rituximab and plerixafor as a mobilization regimen for patients with lymphoma

Previous reports suggested that rituximab may impair stem cell collection and posttransplant engraftment in lymphoma patients undergoing autologous hematopoietic progenitor cell transplantation. A prospective biologic allocation study examined the effect of adding rituximab to a mobilization regimen of plerixafor and granulocyte-colony-stimulating factor (G-CSF) for patients with CD20+ lymphoma compared with CD20- lymphoma patients mobilized without rituximab. The primary endpoint was safety of the rituximab-containing regimen; secondary endpoints compared the efficiency of stem cell collection, posttransplant engraftment, graft characteristics, mobilization kinetics, immune reconstitution, and engraftment durability between the cohorts of patients with CD20+ and CD20- lymphoma. Fifteen subjects assigned to each treatment arm were accrued. Both mobilization regimens had similar toxicities. The median number of CD34+ cells collected (7.4 × 10(6) /kg vs. 6.4 × 10(6) /kg) and the median numbers of days of apheresis needed to collect stem cells were not different between the CD20+ and CD20- cohorts. No significant differences in neutrophil engraftment (median, 13.5 days vs. 13 days) or platelet engraftment (22 vs. 21 days) or in graft durability were seen comparing patients with CD20+ versus CD20- lymphoma. There were no significant differences in the kinetics of blood T-cell or natural killer-cell reconstitution comparing the two groups. B-cell reconstitution was delayed in the CD20+ lymphoma group, but this did not translate into a significant increase in infectious complications. Rituximab can be safely added to the combination of plerixafor and G-CSF as a mobilization strategy without excess toxicity or posttransplant engraftment delays for patients with chemosensitive lymphoma undergoing autologous hematopoietic progenitor cell transplantation.

Hyperbaric oxygen therapy for hematopoietic progenitor cell (HPC) collection in poor mobilizers.

e18576 Background: Currently available agents such as cyclophosphamide or etoposide in combination with G-CSF and plerixafor are effective in mobilizing HPC in most patients with myeloma and refractory lymphoma needing autologous HPC transplant. Unfortunately, there are patients who are unable to mobilize HPC adequately because of prior radiation or stem cell toxic alkylating chemotherapy. As Thom et al. noted an increase in circulating CD34+ cells in patients undergoing hyperbaric oxygen therapy (HBOT) for osteoradionecrosis of the mandible, we examined this modality as a mobilizing agent in those who failed at least one other modality. Methods: A retrospective data review of all patients undergoing HPC mobilization from January 2009 to December 2011 identified 9 patients (7 male, 2 female), (8 multiple myeloma, 1 non-Hodgkin lymphoma) who underwent HBOT for mobilization of HPC after failing to collect at least 2 x 10e6 CD34+ cells/kg CD34 cells/kg body weight following standard mobilization using chemotherapy, G-CSF and/or plerixafor. Mean age was 61 (range 52-82 y). Four had previously undergone autologous transplant. Treatment was in hyperbaric oxygen chambers pressurized with 100% oxygen at 1.5 atmospheres of pressure for 90 minutes per day, with treatment ranging from 3 to 8 days. During this period patients also received growth factors and plerixafor. Results: Total CD34+ cells/kg collected ranged from 0.1 - 20.6 x 10e6 CD34+ cells/kg; 5 patients collected &gt; 2 x 10e6 CD34+ cells/kg, of which 3 collected &gt; 5 x 10e6 CD34+ cells/kg. All patients had failed prior mobilization and collection with G-CSF, and 8 had also previously received plerixafor. One of the patients who had undergone prior tandem transplant collected 8.23 x10e6 CD34+ cells/kg. No patient experienced toxicities known to be associated with use of HBOT such as barotrauma. Conclusions: HBOT appears to be an effective and safe modality to mobilize HPC in patients who are poor mobilizers, when used in conjunction with G-CSF and plerixafor.

Hematopoietic progenitor cell transplantation toxicities in multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw: a longitudinal cohort study

There is no information regarding the toxicity associated with autologous hematopoietic progenitor cell transplantation (AHPCT) in patients with multiple myeloma (MM) who have bisphosphonate-induced osteonecrosis of the jaw (ONJ). There is also limited information regarding long-term outcome of these patients. In this retrospective cohort study, we compared the toxicity after AHPCT in MM patients with and without ONJ. We also analyzed the response rate and overall survival of this population of patients. During the study period, 176 patients underwent AHPCT at our institution for MM. Ten patients with ONJ prior to AHPCT were matched to 40 control patients without ONJ. The incidence and severity of transplantation-associated toxicities were similar in both groups, including mucositis, 50 % in patients with ONJ vs. 68 % in controls (p = 0.889) and febrile days, median 1 vs. 3 days, respectively (p = 0.524). Myeloid engraftment and hospital length of stay were also similar between patients with ONJ and controls. There were significantly more complete remissions in patients with ONJ than in control patients (45 % vs. 15 %, p = 0.0336), but survival between the groups was not significantly different (log-rank p = 0.0818). We conclude that the incidence and severity of transplantation-associated toxicities are similar in MM patients with and without ONJ. Long-term survival was also similar between both groups.

Early Readmission Rates After Autologous and Allogeneic Hematopoietic Progenitor Cell Transplantation (HPCT)

Early Readmission Rates After Autologous and Allogeneic Hematopoietic Progenitor Cell Transplantation (HPCT)

Pharmacists' Role in Implementation of an Allogeneic HPC Transplant Program

The autologous hematopoietic progenitor cell (HPC) transplant program at USC Norris Comprehensive Cancer Center has been in practice since 1987. In 2011, the planning and implementation of allogeneic HPC transplant program began with efforts of a multi-disciplinary team of experts providing collaborative clinical practice. Pharmacists played a key role especially in the creation of policies, preprinted orders, drug therapy management, and education. Pharmacists reviewed medications for the conditioning regimen, graft-versus-host disease (GVHD) prophylaxis, and various supportive cares by evaluating literature and bench-marking with other HPC transplant centers. The goal was to ensure evidence-based practices as well as to meet current regulatory standards. The pharmacists' diligence in procuring and ensuring adequate supply of medications as well as their timely delivery to patients was crucial in light of recent drug shortage challenges. Instituting standing orders for electrolyte replacements, STAT antibiotics, GVHD prophylaxis, and keeping the majority of medications as floor stock items enabled us to achieve this goal. In order to administer high-dose chemotherapy safely, two pharmacists independently verify chemotherapy doses against the standardized regimen listed on the orders. Monographs for key medications containing information such as drug stability, compatibility, and special handling were compiled to provide a quick reference and educational tool for pharmacists. By participating in daily patient rounds, pharmacists monitored patients' clinical status closely, managed complications of high-dose chemotherapy and adjusted levels of anti-GVHD medications in a timely manner. To ensure optimal therapeutic dosing with minimal toxicity, busulfan pharmacokinetics was implemented under joint leadership of pharmacists and nurses. In addition, pharmacists played a major role in educating nurses on high-dose chemotherapy, immunosuppressive agents and the supportive care for infection, mucositis, nausea and vomiting in allogeneic HPC transplant patients. In conclusion, pharmacists played a critical role by providing their expertise in the management of complex drug therapy, monitoring busulfan pharmacokinetics, educating their peers and thus, contributing to the success of the program.

Application of reticulated platelets to transfusion management during autologous stem cell transplantation.

BackgroundThe immature (or reticulated) platelet fraction (IPF) is rich in nucleic acids, especially RNA, and can be used as a predictive factor for platelet recovery in platelet immunomediated consumption or in postchemotherapy myelosuppression. Our aim was to determine if transfusions with IPF-rich solutions, during autologous peripheral blood stem cell transplantation, reduce the occurrence of bleeding and hemorrhagic complications.Patients and methodsTransfusions were administered to 40 children, affected with hematological pathologies, who underwent autologous peripheral hematopoietic progenitor cell transplantation. There were two groups of 20 patients, one group treated with IPF-poor and the other with IPF-rich solutions. In the two groups, the conditioning regimen was the same for the same pathology (hematological pathologies: 14 acute lymphoblastic leukemia; twelve acute myelocytic leukemia; four non-Hodgkin’s lymphoma; two Hodgkin’s lymphoma; eight solid tumors). A new automated analyzer was used to quantify the IPF: the XE2100 (Sysmex, Kobe, Japan) blood cell counter with upgraded software.ResultsThe 20 patients who received solutions with a high percentage of IPF (3%–9% of total number of infused platelets) required fewer transfusions than the 20 patients who received transfusions with a low percentage of IPF (0%–1% of total number of infused platelets): 83 versus 129 (mean of number of transfusions 4.15 versus 6.45) and a significant difference was found between the two groups by using the Mann–Whitney test (P < 0.001). The prophylactic transfusions decreased from three to two per week. There was only one case of massive hemorrhage.ConclusionThe use of IPF solutions reduces the number of transfusions and bleedings after peripheral blood stem cell transplantation in pediatric patients.

Secondary MGUS after autologous hematopoietic progenitor cell transplantation in plasma cell myeloma: a matter of undetermined significance

Plasma cell myeloma, characterized by clonally aberrant plasma cells that produce abnormal monoclonal Igs, is the most common indication for autologous hematopoietic progenitor cell transplantation (AHPCT) in North America. We observed appearance of new monoclonal gammopathies different from the original protein in the post-AHPCT setting and termed this condition 'secondary MGUS' (monoclonal gammopathy of undetermined significance). Hence, we performed a retrospective, single institution review of serum protein electrophoresis/immunofixation electrophoresis data in 92 AHPCT recipients from the period 2000-2009. In all, 22 of 92 patients (24%) undergoing AHPCT met criteria for secondary MGUS. Contrary to previous studies, often referred to as 'abnormal protein banding,' we did not observe this condition as a favorable prognostic indicator in affected patients when compared with the control group (P=0.686). However, we did note that a subgroup of the study cohort who developed secondary MGUS after a prolonged latency (>10 months) had an improved median OS compared with the remainder of the study cohort (75 months vs 41 months, P=0.005). As there have been significant advancements in understanding the pathobiology and clinical significance of MGUS, we believe that secondary MGUS merits dedication of resources for investigation to determine its true clinical relevance, prognostic value and pathophysiology.

CD8+ CD26++ Lymphocytes Are T Memory Cells with T Cell Repopulating Capacity and Are Depleted in the Course of Haematopoietic Progenitor Cell Aphaeresis

Abstract 2989The glycoprotein dipeptidyl peptidase IV (DPP IV, CD26) possesses an enzymatic activity which is crucial for the turnover of chemokines including CCL5/RANTES, CXCL12/SDF-1a, CCL8/MCP-2 and CCL11/Eotaxin. CD26 is primarily expressed on subsets of human lymphocytes as well as on murine splenocytes, thymocytes and decidual lymphocytes. A subpopulation of memory T cells shows a high surface expression of CD26 that has been shown to be related to resolved viral infections, production of interleukin-2, and tissue invasion. Furthermore, CD26 affects the turnover of adenosine, since human CD26 anchors adenosine deaminase (ADA) to the lymphocyte surface.We had shown previously that, in the course of haematopoietic progenitor cell (HPC) aphaeresis, a distinct subset of CD8+CD26++ lymphocytes was enriched in the aphaeresis products to a varying extent. High numbers of these cells in HPC autografts were associated with a poor clinical outcome after autologous HPC transplantation. A phenotypic characterization of CD26++ cells was performed with samples of peripheral blood from healthy donors using multicolor flow cytometric analysis.The characterization of CD26++/CD8+ cells identified these cells as a homogeneous population with a distinct T memory cell phenotype (CD45RO+, CD161++, IL18Ralpha++, CCR7−), consistent with a population of T cells with high rhodamine efflux, chemoresistance and T cell repopulating capacity described before. Conversely, gating of CD45RO+, CD161++, IL18Ralpha++, CCR7− cells yielded a population of cells that were exclusively CD8+ and CD26++.We conclude that CD8+ CD26++ cells define T memory cells with chemoresistance and repopulating capacity as defined by the phenotype: CD45RO+ CD161++ IL18Ralpha++ CCR7−. The observation that the enrichment of these cells in the course of progenitor cell apheresis is associated with poor clinical outcome after PBSCT could be explained by a depletion of these cells from the peripheral blood which could be hazardous. Technical improvements of the apheresis procedure are feasible. Furthermore, the characterization of T memory cells with repopulating capacity as CD8+ CD26++ allows a simple approach for their isolation fur further processing. The quantification of CD8+ CD26++ cells has now been integrated into the routine immunomonitoring to further assess this facet of post-transplantation immune reconstitution and possible correlations with the clinical course after allogeneic stem cell transplantation. Disclosures:No relevant conflicts of interest to declare.

Aldehyde dehydrogenase as an alternative to enumeration of total and viable CD34+ cells in autologous hematopoietic progenitor cell transplantation

We validated the correlation of aldehyde dehydrogenase ALDH(br) cells with total and viable CD34(+) cells in fresh and thawed hematopoietic progenitor cell (HPC) products, and looked for a correlation with time to white blood cell (WBC) and platelet engraftment after autologous transplantation, using simple linear regression analyzes. We found a significant correlation between pre-freeze ALDH(br) cell numbers and pre-freeze total CD34(+) (P < 0.001), viable CD34(+) (P < 0.001) and post-thaw viable CD34(+) (P < 0.001) cell numbers. We suggest that ALDH(br) may be substituted for CD34(+) cell numbers when evaluating HPC. As post-thaw viability testing apparently adds no significant information, we suggest that it may not be necessary. Finally, neither marker correlated with time to engraftment in our patients, supporting previous data suggesting the existence of a threshold dose for timely engraftment around 2.5 × 10(6) cells/kg.

Apheresis‐related enrichment of CD26++ T lymphocytes: phenotypic characterization and correlation with unfavorable outcome in autologous hematopoietic progenitor cell transplantation

The lymphocyte surface glycoprotein CD26 anchors adenosine deaminase to the lymphocyte surface and possesses dipeptidyl peptidase IV activity. A distinct subset of CD26++ lymphocytes in autologous hematopoietic progenitor cell transplants (HPCTs) was investigated with regard to clinical outcome after autologous HPCT. The phenotype of these cells was characterized in more detail. Forty-two eligible patients (multiple myeloma, n = 31; Hodgkin's disease, n = 3; non-Hodgkin's lymphoma, n = 6; peripheral neuroectodermal tumor, n = 1; acute myeloid leukemia, n = 1) were included in a retrospective analysis. Distinct cellular subsets, including CD26+/- and CD26++ subpopulations, were analyzed for correlations with kinetics of engraftment, progression-free survival, and overall survival. The numbers of CD26++ T lymphocytes in the autograft correlated inversely with progression-free survival (p = 0.013). CD26++ T lymphocytes transfused per kg of body weight were predictive for the occurrence of disease progression or relapse (p = 0.006). Importantly, the numbers of CD26++ cells showed a highly variable degree of enrichment in the autograft, but no significant variations in the peripheral blood before apheresis. The characterization of CD26++ cells revealed that CD26++/CD8+ cells form a homogeneous population with a distinct T memory cell phenotype (CD45RO+, CD161++, interleukin-18Rα++, CCR7-). CD26++ lymphocytes define a discrete phenotype of T memory cells with known chemoresistance and T-cell-repopulating capacity. Their enrichment during apheresis and corresponding depletion from the circulation are associated with an adverse outcome in autologous HPCT.

“Secondary MGUS” After High-Dose Melphalan and Autologous Hematopoietic Progenitor Cell Transplantation In Multiple Myeloma: A Matter of Undetermined Significance.

AbstractAbstract 1296New monoclonal gammopathies (secondary MGUS) sometimes appear after autologous hematopoietic progenitor cell transplantation (AHPCT) for multiple myeloma (MM). While the pathophysiology and prognostic significance of this phenomenon is incompletely defined, previously published series hypothesize that this phenomenon is due to recapitulation of early B-cell ontogeny, and suggest that it confers a more favorable prognosis.[1-3] We retrospectively reviewed immunoelectrophoretic data on MM patients who underwent AHPCT at University Hospitals Case Medical Center from January 2000 - May 2009, searching for development of secondary MGUS after AHPCT. Secondary MGUS was defined as the occurrence of a monoclonal gammopathy of a different isotype (i.e. change in either the heavy chain, light chain, or both) than the patient's previously identified MM-associated monoclonal gammopathy at any time point after AHPCT.We identified 89 MM patients who underwent AHPCT during that period. All patients received pre-transplant conditioning with melphalan 200 mg/m2 +/− TBI. Eighteen patients (20%) subsequently developed one or more secondary MGUS. There was no significant difference in age, gender, and stage of disease between patients who developed a secondary MGUS and those who did not (p=0.88). No patients who developed secondary MGUS had light-chain only disease at diagnosis. Nine patients developed a single new isotype, nine patients developed two or more new isotypes. The maximum number of new isotypes of monoclonal gammopathy in a single patient was six. Time to development of a secondary MGUS (latency) was highly variable, from 1.9 to 63.9 months, with a median of 10.5 months. One-third (33.3%) of patients who developed secondary MGUS developed their new isotype or isotypes more than a year after AHPCT. Amongst patients with secondary MGUS, the number of secondary isotypes was predictive of overall survival (OS). The hazard of death was 2.04 times higher with one increase of isotype (p = 0.016). There was a statistically significant association between latency to developing secondary MGUS and OS; for patients with latency ≤10 months, the median OS was 38 months, compared to 74 months for those with latency > 10 months (p = 0.023).Secondary MGUS is a phenomenon observed in a substantial subset of patients undergoing AHPCT for MM. Our study demonstrates that this phenomenon cannot be entirely attributed to immune reconstitution, as previously postulated, as one-third of patients developed secondary MGUS a year or more after AHPCT. While selection bias may explain why patients who have longer latency to secondary MGUS have significantly better overall survival, further study is needed to clarify predictors of developing secondary MGUS and the pathophysiology underlying this phenomenon. [Display omitted] 1. Maisnar, V., et al., Isotype class switching after transplantation in multiple myeloma. Neoplasma, 2007. 54(3): p.225-8.2. Zent, C.S., et al., Oligoclonal protein bands and Ig isotype switching in multiple myeloma treated with high-dose therapy and hematopoietic cell transplantation. Blood, 1998. 91(9): p.3518-23.3. Mitus, A.J., et al., Monoclonal and oligoclonal gammopathy after bone marrow transplantation. Blood, 1989. 74(8): p. 2764-8. Disclosures:No relevant conflicts of interest to declare.

Intravenous Compared to Oral Busulfan with Cyclophophamide for Allogeneic Hematopoietic Progenitor Cell Transplant Conditioning for AML and MDS.

AbstractAbstract 3475Busulfan (Bu) is commonly used with cyclophosphamide (Cy) as a conditioning regimen for allogeneic hematopoietic progenitor cell transplantation (HPCT). Recently, intravenous (IV) Bu has often replaced oral Bu for conditioning. We have previously reported that substituting IV for oral Bu was associated with a lower rate of relapse, and superior relapse-free and overall survivals for relapsed or refractory non-Hodgkin lymphoma patients undergoing autologous HPCT (Dean et al. Br J Haematol 2010 Jan;148(2):226-34). We retrospectively compared the outcomes of 135 consecutively treated AML and MDS patients who underwent allogeneic HPCT at our institution from 5/2001 through 10/2009 with BuCy using oral (n = 93) or IV (n = 42) Bu, without dose adjustment. The analysis included matched related (n=97) and 8/8 HLA matched unrelated donors (n=38). Oral Bu was administered as 1 mg/kg every 6 hours for 16 doses while IV Bu was administered as 0.8 mg/kg every 6 hours for 16 doses (days –8 through -4) followed by Cy 60 mg/kg/day × 2 (days –3 and –2). The IV Bu patients were older (median age 49 vs. 47 yrs, respectively, p=0.037), more commonly had unrelated donors and peripheral blood stem cells for their HPCT cell source than those treated with oral Bu. There were no significant differences between the groups with regards to patient gender, race, CIBMTR comorbidity index score, number of prior chemotherapy regimens, pre-transplant disease status (each group had 45% of patients in CR1 or CR2), donor-recipient gender relationships or nucleated cell dose infused. The IV Bu group had a higher median CD34+ cell dose infused than those who received oral Bu (3.34 vs. 2.19 ×106/kg, respectively, p=0.028). The IV Bu patients experienced a significantly lower incidence of mucositis (3% vs. 55%, p<0.001) and less severe mucositis (median OMAS scores 0 vs.0.08, respectively, p<0.001). However, there were no significant differences between the IV and oral Bu groups in days until neutrophil and platelet count engraftment, length of transplant hospitalization, incidence of acute or chronic GVHD, sinusoidal obstruction syndrome, and 100 day mortality. At this time 26 (62%) of the IV Bu patients and 33 (36%) of the oral Bu patients are alive, however, the median follow-up was substantially longer for the oral Bu group (50 vs. 13 months, p<0.001). Disease relapse was the most common cause of death for both the IV and oral Bu patients accounting for approximately 50% of deaths in each group. The 1 and 2 year transplant-related mortality for the IV Bu patients was 21% for both, while that for the oral Bu group was 23% and 29%, respectively. The 1 and 2 year relapse mortality for the IV Bu patients was 21% for both, while that for the oral Bu group was 24% and 29%, respectively. Substituting IV for oral Bu reduces variability in drug exposure and potentially improves safety as suggested from our finding of significantly less severe oral mucositis in the IV Bu group. Further follow-up of the IV Bu group is required to adequately assess for a survival benefit. Whether pharmacokinetic-based Bu dosing can improve outcomes after allogeneic HPCT in this setting is worthy of further study. Disclosures:Sobecks:Otsuka Pharm.: Research Funding.

Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962

This prospective study was designed to determine the safety and efficacy of cyclophosphamide, BCNU, and etoposide (CBV) conditioning and autologous peripheral blood stem cell transplant (PBSCT) in children with relapsed or refractory Hodgkin and non-Hodgkin lymphoma (HL and NHL). Patients achieving complete remission (CR) or partial remission (PR) after 2 to 4 courses of reinduction underwent a granulocyte-colony stimulating factor (G-CSF) mobilized PBSC apheresis with a target collection dose of 5 × 10⁶ CD34(+)/kg. Those eligible to proceed received autologous PBSCT after CBV (7200 mg/m², 450-300 mg/m², 2400 mg/m²). Forty-three of 69 patients (30/39 HL, 13/30 NHL) achieved a CR/PR after reinduction. Thirty-eight patients (28 HL, 10 NHL) underwent PBSCT. All initial 6 patients who received BCNU at 450 mg/m² experienced grade III or IV pulmonary toxicity compared to none of the subsequent 32 receiving 300 mg/m² (P < .0001). The probability of overall survival (OS) at 3 years for all patients is 51% and for transplanted patients is 64%. The 3-year event-free survival (EFS) is 38% (45% for HL; 30% NHL). The 3-year EFS in transplanted patients is 66% (65% HL; 70% NHL). Initial duration of remission of ≥12 versus <12 months was associated with a significant increase in OS (3 years OS 70% versus 34%) (P = .003). BCNU at 300 mg/m(2) in a CBV regimen prior to PBSCT is well tolerated in relapsed or refractory pediatric lymphoma patients. A short duration (<12 months) of initial remission is associated with a poorer prognosis. Last, a high percentage of patients achieving a CR/PR after reinduction therapy can be salvaged with CBV and autologlous PBSCT.