Comparison of myeloablative and reduced intensity conditioning unrelated donor allogeneic peripheral blood stem cell transplant outcomes for AML using thymoglobulin for GVHD prophylaxis.

A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.

R-BEAM versus Reduced-Intensity Conditioning Regimens in Patients Undergoing Allogeneic Stem Cell Transplantation for Relapsed Refractory Diffuse Large B Cell Lymphoma.

Allogeneic stem cell transplant (alloSCT) is considered in diffuse large B cell lymphoma (DLBCL) patients with chemorefractory disease or who have relapsed after autologous SCT. Here we present the first report of alloSCT using the R-BEAM (rituximab, carmustine, etoposide, cytarabine, melphalan) conditioning regimen in DLBCL patients. We retrospectively compared long-term alloSCT outcomes of DLBCL patients who received either R-BEAM (n = 47) or reduced-intensity conditioning (RIC) regimens (n = 23). Seventy patients (median age, 53 years) with DLBCL received alloSCT between January 2005 and December 2017. The median number of pretransplant therapies was 3, and 17 patients (24%) received prior autologous SCT. All received rituximab as a frontline or salvage therapy before alloSCT. The donor was unrelated in 42 patients (60%), and peripheral blood stem cells were commonly used (96%). The 6-month cumulative incidence of grades III to IV acute graft-versus-host disease (GVHD) was 36.2% and 8.7% for R-BEAM and RIC, respectively (P = .03). Median follow-up of surviving patients after R-BEAM and RIC was 3.1 and 5.5 years, respectively. Three-year overall survival (OS) after R-BEAM and RIC was 34.4% and 43.4%, respectively (P = .48). At 3 years, R-BEAM was associated with a similar relapse rate (25.5% versus 26.1%, P = .96), nonrelapse mortality (NRM; 39.7% versus 39.1%, P = .98), and relapse-free survival (RFS; 34.8% versus 34.7%, P = .75) compared with RIC. In multivariable analysis lower Karnofsky performance score was associated with lower OS (hazard ratio, .96; P = .05), whereas chemorefractory disease was associated with a higher relapse risk (hazard ratio, 8.8; P = .04). No difference in OS, relapse, NRM, or RFS was noticed between R-BEAM and RIC. R-BEAM regimen seems to be feasible and results in equivalent rates of long-term OS, relapse, NRM, and RFS compared with RIC. However, a significantly higher rate of severe acute GVHD was noticed.

Clinical outcomes of multiple myeloma patients who undergo autologous hematopoietic stem cell transplant with G-CSF or G-CSF and plerixafor mobilized grafts.

Impact of Plerixafor (P) mobilized stem cells on immune reconstitution, such as absolute lymphocyte count at day 30 (ALC30), and on long-term outcomes of Multiple Myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) has not been well established. We evaluated total of 469 patients mobilized with G-CSF (G) alone, and 141 patients mobilized with G-CSF plus plerixafor (G+ P). Patients only received plerixafor if they had peripheral blood CD34+ blood count <20/µL on first planned day of collection. Primary endpoint, ALC30, was 1.3 K/µL (range, 0.1-4.5) and 1.2 K/µL (range, 0.1-5.1) for G and G + P, respectively (P =. 61). The median PFS was 2.5 years (95% CI, 2.1-3.2) and 2.8 years (95% CI, 2.0-3.3) for G and G + P, respectively (HR: 1.13; 95% CI, 0.84-1.50; P = .42). The median OS was 6.1 years (95% CI, 4.6-NR) for G group compared to 3.7 years (95% CI, 3.2-NR) for the G + P group (HR: 1.64; 95% CI, 1.12-2.40; P = .01). The median follow-up time for OS was 2.53 years (95% CI, 2.13-2.99) and 1.59 years (95% CI, 1.17-2.02) for G and G+ P group, respectively. In this large retrospective analysis of MM patients mobilized with G-CSF vs G-CSF + P, there was no significant difference in lymphocyte recovery or PFS. There was an overall survival difference in patients who were poor mobilizers and could not be mobilized with G-CSF alone.

Liver Graft-Versus-Host Disease is associated with poor survival among allogeneic hematopoietic stem cell transplant recipients.

Liver Graft-versus-host disease (GVHD) is common in patients with post-transplant liver dysfunction following allogeneic hematopoietic stem cell transplantation (AHSCT). Oftentimes, the diagnosis is made clinically, and liver biopsy is deferred. Our objective was to evaluate the risk factors and clinical outcomes of liver GVHD among patients who developed post-transplant liver dysfunction. Additionally, we evaluated the feasibility of liver biopsy in this population. We compared outcomes between liver GVHD and a "non-liver GVHD" group, which consisted of other etiologies of post-transplant liver dysfunction. Between January 2003 and December 2010, 249 patients developed post-transplant liver dysfunction following AHSCT: 124 patients developed liver GVHD and 125 were in the "non-liver GVHD" group. The incidence of acute and chronic liver GVHD at one year was 15.7% and 31.0%, respectively. The competing risk analysis revealed full intensity conditioning regimen (Hazard ratio [HR], 1.76; P = .008) and related donor (HR, 1.68; P = .004) as independent risk factors for liver GVHD. The time-varying covariate Cox regression analysis with competing risk event, demonstrated that liver GVHD was independently associated with higher non-relapse mortality, and adverse relapse-free and overall survival. A total of 112 liver biopsies were performed in 100 patients. No major complications were observed. Liver biopsy confirmed prebiopsy hypotheses in 49% of cases, and led to treatment modification in 49% of patients. Our study shows that liver GVHD is associated with adverse survival. Liver biopsy is safe and often helps directing care in this setting.

Fluoroquinolone prophylaxis in autologous hematopoietic stem cell transplant recipients.

PURPOSE: Although fluoroquinolone prophylaxis is frequently utilized in autologous hematopoietic stem cell transplant (AHSCT) patients, its impact on morbidity and mortality is uncertain. This study investigates the role of quinolone prophylaxis after AHSCT in recent years. METHODS: We conducted a retrospective review of 291 consecutive adult patients who underwent AHSCT for malignant disorders, between June 2013 and January 2015. Outcomes were compared between patients who received norfloxacin prophylaxis and those who did not. The endpoints were mortality during prophylaxis and at 100 days after transplant, frequency of ICU admissions, and incidence and type of bacteremia. RESULTS: Of 291 patients, 252 patients received norfloxacin prophylaxis and 39 patients did not. The mortality during prophylaxis and at 100 days as well as the median number of days of hospitalization following AHSCT did not differ between the two groups. No differences were noted in the frequency of ICU admission, incidence of septic shock, and duration of ICU stay. Patients who did not receive prophylaxis had a significantly higher rate of neutropenic fever (97%) than patients who received prophylaxis (77%) (p = 0.005). The patients with prophylaxis demonstrated a significantly higher rate of gram-positive bacteremia as compared to those without prophylaxis (p = 0.002). Frequency of Clostridium difficile infection was similar during and post-prophylaxis. More antibiotic use was noted among patients without prophylaxis [97%; median 9 (range, 5-24) days] compared to patients with prophylaxis [79%; median 7 (range, 3-36) days, p = 0.04]. CONCLUSION: Although fluoroquinolone prophylaxis reduced the incidence of neutropenic fever and antibiotic use in AHSCT, it did not alter mortality or morbidity.

Targeting CD138-/CD20+ Clonogenic Myeloma Precursor Cells Decreases These Cells and Induces Transferable Antimyeloma Immunity.

This phase Ib clinical trial evaluated whether pretargeting of CD20(+) clonogenic myeloma precursor cells (CMPCs) with anti-CD3 × anti-CD20 bispecific antibody-armed T cells (BATs) before autologous stem cell transplantation (SCT) in patients with standard-risk and high-risk multiple myeloma would induce antimyeloma immunity that could be detected and boosted after SCT. All 12 patients enrolled in this study received 2 BATs infusions before SCT, and 4 patients received a booster infusion of BATs after SCT. Pretargeting CD138(-)/CD20(+) CMPCs with BATs before SCT was safe and reduced levels of CMPCs by up to 58% in the postinfusion bone marrow in patients who remained in remission. Four of 5 patients who remained in remission had a >5-fold increase in IFN-γ enzyme-linked immunospot responses. SOX2 antibody increased after BATs infusions and persisted after SCT. The median anti-SOX2 level at 3 months after SCT was 28.1 ng/mL (range, 4.6 to 256 ng/mL) in patients who relapsed and 46 ng/mL (range, 28.3 to 73.3 ng/mL) in patients who remained in remission. The immune correlates suggest that infusions of targeted T cells given before SCT were able to reduce CMPC levels and induced cellular and humoral antimyeloma immunity that could be transferred and boosted after SCT.

Incidence, etiology, and outcome of pleural effusions in allogeneic hematopoietic stem cell transplantation.

Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity-mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 - 869) post-HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 - 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, ≤7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341-E347, 2016. © 2016 Wiley Periodicals, Inc.

Incidence, risk factors, and outcome of cytomegalovirus viremia and gastroenteritis in patients with gastrointestinal graft-versus-host disease.

Gastrointestinal (GI) graft-versus-host disease (GVHD) is one of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia at a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P < .001). The incidence of CMV viremia with relation to donor (D) and recipient (R) CMV serostatus subgroups was as follows: D+/R+, 73%; D-/R+, 67%; D+/R-, 19%; and D-/R-, 0. A total of 31 patients were diagnosed with a biopsy-proven CMV gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D-/R+, 31%; D+/R-, 12%; and D-/R-, 0. Median follow-up time for the 252 patients was 35.4 (95% CI 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P < .001) and development of CMV gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis.

High incidence of severe acute graft-versus-host disease with tacrolimus and mycophenolate mofetil in a large cohort of related and unrelated allogeneic transplantation patients.

Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patient's age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.

Successful hematopoietic stem cell collection in patients who fail initial plerixafor mobilization for autologous stem cell transplant.

We report our experience of collecting stem cells in patients who failed to mobilize sufficient hematopoietic stem cell (HSC) using plerixafor (P) in the initial mobilization attempt. Twenty four patients were identified who failed a first mobilization attempt using P. Of these, 22 patients received granulocyte colony stimulating factor (G-CSF) and two patients received cyclophosphamide (CY) + G-CSF in combination with P for the initial attempt. The agents used for second collection attempt were granulocyte macrophage colony stimulating factor (GM-CSF) + G-CSF (19 patients), G-CSF + P (three patients), CY + G-CSF (one patient), and bone marrow harvest (one patient). A median of 0.6 × 10(6) CD34(+) cells/kg (range 0-1.97) were collected in the initial attempt. A second collection was attempted at a median of 22 days (range 15-127) after the first failed mobilization. The median CD34(+) cell dose collected with the second attempt was 1.1 × 10(6) CD34(+) cells/kg (range 0-7.2). A third collection was attempted in six patients at median of 51 days (range 34-163) after the first failed mobilization. These patients collected a median of 1.1 × 10(6) CD34(+) cells/kg (range 0-6.5). Total of 16 patients (67%) collected sufficient cells to undergo autologous stem cell transplant and eight patients (33%) were able to collect ≥2 × 10(6) CD34(+) cells/kg in a single subsequent attempt. Our experience suggests that a majority of patients who fail primary mobilization despite use of P can collect sufficient HSC with a subsequent attempt using combination of G-CSF with either P or GM-CSF.

A phase I dose-escalation trial of high-dose melphalan with palifermin for cytoprotection followed by autologous stem cell transplantation for patients with multiple myeloma with normal renal function.

Melphalan 200 mg/m(2) is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day -2 began at 200 mg/m(2) with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day -5, -4, and -3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m(2) increments up to a maximum dose of 280 mg/m(2). Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥ grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥ grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m(2) did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m(2). Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m(2), thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.

CD20-targeted T cells after stem cell transplantation for high risk and refractory non-Hodgkin's lymphoma.

A phase I trial of infusing anti-CD3 × anti-CD20 bispecific antibody (CD20Bi) armed activated T cells (aATC) was conducted in high-risk/refractory non-Hodgkin's lymphoma patients to determine whether aATC infusions are safe, affect immune recovery, and induce an antilymphoma effect. Ex vivo expanded ATC from 12 patients were armed with anti-CD20 bispecific antibody, cryopreserved, and infused after autologous stem cell transplantation (SCT). Patients underwent SCT after high-dose chemotherapy, and aATC infusions were started on day +4. The patients received 1 infusion of aATC per week for 4 weeks after SCT with doses of 5, 10, 15, and 20 × 10(9). aATC infusions were safe and did not impair engraftment. The major side effects were chills, fever, hypotension, and fatigue. The mean number of IFN-γ Enzyme-linked Immunosorbent Spots (ElSpots) directed at CD20 positive lymphoma cells (DAUDI, P = .0098) and natural killer cell targets (K562, P < .0051) and the mean specific cytotoxicity directed at DAUDI (P = .037) and K562 (P = .002) from pre-SCT to post-SCT were significantly higher. The increase in IFN-γ EliSpots from pre-SCT to post-SCT in patients who received armed ATC after SCT were significantly higher than those in patients who received SCT alone (P = .02). Serum IL-7, IL-15, Macrophage inflammatory protein (MIP)-1 beta, IP-10, MIP-1α, and Monokine induced by gamma interferone increased within hours after infusion. Polyclonal and specific antibodies were near normal 3 months after SCT. aATC infusions were safe and increased innate and specific antilymphoma cell immunity without impairing antibody recovery after SCT.

Evaluating the effects of lenalidomide induction therapy on peripheral stem cells collection in patients undergoing autologous stem cell transplant for multiple myeloma.

INTRODUCTION: Lenalidomide (LEN) is a relatively new and very effective therapy for multiple myeloma (MM). Prior LEN therapy is associated with an increased risk of peripheral blood stem cell collection (PBSC) failure, particularly with filgrastim (G-CSF) alone. We performed a retrospective chart review of 319 consecutive MM patients who underwent apheresis to collect PBSCs for the first autologous stem cell transplant (ASCT). RESULTS: The median number of PBSCs collected in the LEN (+) group was significantly less than the LEN (-) group (6.34 vs. 7.52 × 10(6) CD34(+) cells/kg; p = 0.0004). In addition, the median number of apheresis sessions required for adequate PBSCs collection were significantly more in the LEN (+) group as compared to LEN (-) group (2 vs. 1 sessions; p = 0.002). In the LEN (+) group, there was a negative correlation between PBSCs collected and prior number of cycles of LEN (p = 0.0001). Rate of PBSC collection failure was 9% in the LEN (+) group and 5% in the LEN (-) group (p = 0.16). Only six patients who failed PBSC collection with G-CSF were able to collect adequate PBSCs with G-CSF + plerixafor. LEN exposure had no effect on neutrophil or platelet recovery post-ASCT. CONCLUSIONS: Up to four cycles of LEN exposure have minimal negative impact on PBSC collection. Despite prolong exposure of LEN, PBSC collection was adequate for two ASCTs in the majority of patients and post-ASCT engraftment was not longer than expected; however, clinical relevance (complication rate, quality of life, cost) of prolonged LEN exposure on both PBSC and ASCT, should be evaluated in prospective clinical trials.

Impact of Pre-transplant Induction Therapy on Outcomes of Patients Who Undergo Autologous Stem Cell Transplantation for Mantle Cell Lymphoma in First Complete Remission.

Mantle cell lymphoma is a rare subtype of non-Hodgkin's lymphoma with poor prognosis and continue to be challenging to treat. The choice of first line induction regimen remains a topic of debate due paucity of clinical trials. We retrospectively evaluated 66 patients diagnosed with mantle cell lymphoma who achieved first complete response after induction chemotherapy followed by autologous stem cell transplant. Treatment groups were divided into low-intensity versus high-intensity regimens. Our data showed the intensity of induction regimen does not impact posttransplant outcomes of mantle cell lymphoma who underwent autologous stem cell transplant in first complete response.

Allogeneic stem cell transplant outcomes between TBI-containing reduced intensity and myeloablative conditioning regimens for ALL in complete remission.

Total-body irradiation (TBI)-based conditioning regimen is preferred in acute lymphoblastic leukemia (ALL). We retrospectively evaluated allogeneic stem cell transplant (alloSCT) outcomes of 86 adult ALL patients in complete remission (CR) who received TBI-containing reduced intensity (RIC) (Flu/Mel/TBI = 31) and myeloablative conditioning (MAC) (VP16/TBI = 47; CY/TBI = 8) between January 2005 and December 2019. All patients received peripheral blood allografts. Patients in the RIC group were older than the MAC group (61 years old versus 36 years, p < .001). Donor was 8/8 HLA-matched in 83% and unrelated in 65% of patients. Three-year survival was 56.04% for RIC and 69.9% for MAC (HR 0.64; p = .19). Propensity score-based multivariable Cox analyses (PSCA) did not demonstrate any difference in grade III-IV acute graft versus host disease (GVHD) (SHR 1.23, p = .91), chronic GVHD (SHR 0.92, p = .88), survival (HR 0.94, p = .92), and relapse-free survival (HR 0.66, p = .47) between both groups, while relapse rate was lower (SHR 0.21, p = .02) for MAC compared to RIC. Our study did not demonstrate any difference in survival for TBI-containing RIC and MAC alloSCT for adult ALL in CR.

Melphalan 180 mg/m2 can be safely administered as conditioning regimen before an autologous stem cell transplantation (ASCT) in multiple myeloma patients with creatinine clearance 60 mL/min/1.73 m2 or lower with use of palifermin for cytoprotection: results of a phase I trial.

UNLABELLED: High-dose melphalan 140 mg/m2 is the standard of care for patients with multiple myeloma (MM) with renal insufficiency (RI). Palifermin as a cytoprotective agent has demonstrated efficacy in reducing the intensity and duration of oral mucositis (OM) in patients who receive intensive chemotherapy/radiotherapy. There is no prospective data on the use of palifermin in patients with MM with RI. ELIGIBILITY CRITERIA: creatinine clearance ≤60 mL/minute/1.73 m2, age >18 years, no dialysis, no active OM, and a suitable candidate for autologous stem cell transplant (ASCT). Melphalan dose ranged from 140 to 200 mg/m2 and escalated at the increment of 20 mg/m2. Six dosages of palifermin 60 mcg/kg/day were given intravenously between day -5 to day +3. Dose escalations were to stop if dose-limiting toxicities (DLTs) occurred at melphalan dose in ≥2 of 3 patients, with that dose declared as the maximal administered dose and the level below where ≤1 of 6 patients had DLTs was considered the maximally tolerated dose (MTD). Nineteen patients were enrolled from June 2007 to June 2011. Data on 15 evaluable patients is reported as 4 patients were removed. Median age was 59 years (range, 36-67 years). The overall incidence of OM ≥ grade 3 was 53% (8 of 15) and a median duration of ≥grade 3 OM was 6.5 days (range, 3-42 days). One patient in L2 (melphalan 160 mg/m2) developed atrial fibrillation on day +9. Two patients in L4 (melphalan 200 mg/m2) developed grade 4 OM, hence reaching DLT. No DLT was observed in 6 patients enrolled in L3 (melphalan 180 mg/m2). Palifermin has permitted safe dose escalation of melphalan up to 180 mg/m(2) in patients with RI.

Anti-thymocyte globulin (thymoglobulin), tacrolimus, and sirolimus as acute graft-versus-host disease prophylaxis for unrelated hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality in patients undergoing unrelated hematopoietic stem cell transplantation. We prospectively evaluated the efficacy of intermediate-dose rabbit anti-thymocyte globulin (Thymoglobulin® a total of 4.5 mg/kg given over days -3, -2, and -1) in combination with tacrolimus and sirolimus for the prevention of aGVHD. We enrolled 47 recipients who underwent unrelated hematopoietic stem cell transplantation. Patients received daily granulocyte colony-stimulating factor starting on day +6 until neutrophil engraftment (median duration, 11 days; range, 9-15 days). Twenty-two patients received HLA 8/8 and 25 received 7/8 matched grafts, respectively. The median follow-up duration was 23.6 months (range, 18.8-27.9 months). The cumulative incidence of grade II to IV aGVHD was 23.4% (95% confidence interval, 12.4-36.3). At 2-year follow-up, the cumulative incidence of nonrelapse mortality was 31.9%, cumulative incidence of relapse was 24.6%, and cumulative incidence of chronic GVHD was 33%. Progression-free survival at 1 year was 54%, with a median of 17.7 months. Overall survival at 1 year was 65%, with no median reached. These results suggest that the combination of Thymoglobulin, tacrolimus, and sirolimus in patients undergoing unrelated hematopoietic stem cell transplantation is well tolerated and associated with a low incidence and severity of aGVHD and chronic graft-versus-host disease.

Aprepitant for prevention of nausea and vomiting secondary to high-dose cyclophosphamide administered to patients undergoing autologous peripheral blood stem cells mobilization: a phase II trial.

This is a phase II trial evaluating efficacy and safety of aprepitant (AP) in combination with 5-HT3 antagonist and adjusted dose dexamethasone in patients receiving high-dose cyclophosphamide (CY) and filgrastim for stem cell mobilization. We used Simon's optimal two-stage design constrained to fewer than 40 patients with 10% type I error and 85% statistical power. The first stage of the study required accrual of 18 response-evaluable patients. The primary endpoint was the control of vomiting without the use of any rescue anti-emetics at 24 h after the administration of high dose CY (4 g/m(2)). If emesis was controlled in ≥9 patients, an additional cohort of 17 patients would be enrolled. The null hypothesis would be rejected if there were ≥20 responses among 35 patients. Forty patients were enrolled, five of whom were not evaluable for response. Eighteen evaluable patients were enrolled in the first stage. Acute emesis was controlled in 10 patients; therefore, enrollment proceeded to stage 2. An additional 17 patients were enrolled; 20/35 response-evaluable patients (57%) did not develop acute vomiting or require rescue anti-emetics, thus achieving the goal of the study. A total of 22/35 response-evaluable patients (63%) met the secondary endpoint of delayed emesis control (days 2-5). Thirty-three out of 35 patients underwent successful stem cell mobilization. No ≥ grade 3 AP-related adverse events were noted. The AP regimen can effectively control acute and delayed emesis in the majority patients receiving high-dose CY.

Role of High-Dose Adjuvant Chemotherapy Followed by Autologous Stem Cell Transplantation in Locally Advanced Triple-Negative Breast Cancer: A Retrospective Chart Review.

Purpose: Women with locally advanced/high-risk triple-negative breast cancer treated with the current standard chemotherapy continue to have a poor prognosis. High-dose chemotherapy with autologous stem cell transplant as treatment for locally advanced/high-risk breast cancer remains controversial due to a lack of survival benefit seen in previous phase III trials. However, these trials evaluated a heterogeneous group of patients with different receptor subtypes. A marginal benefit was observed in certain subgroups. We report long-term outcomes of women with stage IIB or III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant at our institution between 1995 and 2001. Methods: This is a retrospective analysis of stage IIB or stage III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant. We excluded women with hormone-positive, HER2/neu-positive/unknown, and/or metastatic disease prior to transplant as per updated AJCC 7th edition guidelines. Patients underwent surgery and either neoadjuvant or adjuvant anthracycline and taxane-based chemotherapy and then proceeded to high-dose chemotherapy and autologous stem cell transplant using carmustine 600 mg/sqm, cyclophosphamide 5.6gm/sqm, and cisplatin 165 mg/sqm (STAMP 1 regimen) for consolidation. This was followed by locoregional breast and lymph node radiation per standard of care. Results: Twenty-nine women (2 stage IIB and 27 stage III) were evaluated. The median age at diagnosis was 43 years (IQR: 40, 51). Eleven patients had 4-9 regional lymph nodes (LN) involved and 16 had 10+ involved LNs. Four patients had T4 or inflammatory breast cancer and two had ipsilateral supraclavicular LNs involved. The median follow-up time is 16 years (95% CI: 12, 19, range <1-19 y) posttransplant. The median overall survival was 15 years (95% CI: 3, 19); the median DFS was 14 years (95% CI: 1, 19). Conclusions: This study of locally advanced/high-risk triple-negative breast cancer treated with adjuvant high-dose chemotherapy and autologous stem cell transplant reveals high overall survival rate. With the current improvement in treatment-related mortality, re-evaluating this approach in this subset of high-risk breast cancer in prospective randomized studies may be worthwhile.