Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.

Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.

Continuous infusion cyclophosphamide and low-dose total body irradiation is a safe and effective conditioning regimen for autologous transplant in multiple myeloma.

We present the results of a novel conditioning regimen in multiple myeloma (MM) patients undergoing tandem autologous stem cell transplant (ASCT). MM patients were enrolled in a prospective phase II clinical trial. After initial ASCT, disease response was assessed by day +100. Patients achieving very good partial remission (VGPR) were offered maintenance therapy. If patients achieved VGPR, they were offered a second ASCT using continuous intravenous cyclophosphamide (CICy) 6 g/m(2) over 4 days and low-dose total body irradiation (ldTBI) 600 rads over 2 days. Total body irradiation was replaced by melphalan 140 mg/m(2) if patients had received prior radiation. Twenty-one patients received tandem ASCT. Three patients received CICy and melphalan. Median duration of neutropenia with CICy/ldTBI was 11 days. Fifteen patients (71.4%) developed febrile neutropenia while grade 1 to 2 diarrhea was the next most common adverse event (42.9%). There was no treatment-related mortality. Four patients had entered complete remission (19%) and 6 achieved VGPR (28.6%). In conclusion, this conditioning regimen is safe and effective and may be useful in patients who do not benefit from first ASCT using more traditional conditioning regimen.

Extramedullary disease in plasma cell myeloma: the iceberg phenomenon.

Extramedullary (EM) plasmacytomas (EMPs) that are not progression of intramedullary (IM) plasma cell myeloma (PCM) are usually indolent. In contrast, EM spread of IM PCM is associated with a poor prognosis. The recently introduced Durie-Salmon PLUS staging system includes EM disease in the poor prognosis category. One study noted an increase in EM disease both at diagnosis and during follow-up of PCM in 2000-2007 compared with previous years raising concerns that adoption of novel agents (thalidomide, lenalidomide and bortezomib) and greater use of hematopoietic cell transplantation (HCT) might be contributory to this. It is uncertain if this is a true increase or merely greater detection due to the increasing use of more sensitive imaging techniques (computerized tomography, magnetic resonance imaging and ¹8F-fluorodeoxyglucose positron emission tomography) or a reflection of the evolving natural history of PCM in an era when patients are living longer (median overall survival before 1996 was 29.9 months vs 44.8 months after 1996). Recent studies suggest there are important biological differences between PCM with or without EM spread that are offering clues that might explain the propensity for dissemination and a more aggressive clinical course. For example, EM relapse in PCM with and without deletion 13 was 30.8 vs 5.6%, suggesting the biology of a plasma cell subclone before HCT can affect the nature of the relapse after HCT. This article will explore the clinical, biological and treatment implications of EM spread of PCM. In addition, the impact of extramedullary disease on the outcomes of autologous and allogeneic HCT for PCM will be analyzed. Allogeneic HCT early in the course of high-risk PCM with EM disease is a consideration since graft vs myeloma effects may be essential to achieve maximal survival benefits.

Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw.

Bisphosphonate induced osteonecrosis of the jaw (BONJ) is a complication in patients taking bisphosphonate (BP) that affects their quality of life and compliance. In this cohort study, patients with multiple myeloma (MM) on intravenous BP therapy were enrolled over 1 year. Demographic and clinical data and genotyping of 10 single nucleotide polymorphisms (SNPs) from seven candidate genes associated with drug or bone metabolism were determined. Of the 78 patients enrolled, 12 had BONJ. The median time to developing BONJ was 28 months. Univariate and multivariate analysis revealed a significant association between BONJ and smoking (p=0.048) and type of BP treatment (p=0.03). A trend for higher odds for BONJ was found for SNPs in five genes: COL1A1 (rs1800012), RANK (rs12458117), MMP2 (rs243865), OPG (rs2073618) and OPN (rs11730582). Considering all five SNPs together, patients with genotype scores ≥ 5 had a BONJ event rate of 57%; those with scores < 5 had a rate of 10%. The adjusted odds ratio was 11.2 (95% confidence interval of 1.8-69.9; p value 0.0097). Smoking, type of BP and combined genotype score of COL1A1, RANK, MMP2, OPG and OPN were significantly associated with BONJ in MM patients undergoing BP therapy.

Reduced-intensity conditioning using fludarabine with either antithymocyte globulin and BU, or low-dose TBI allowing allogeneic hematopoietic SCT.

In a single-center study, we analyzed the outcomes of 66 patients with advanced hematological malignancies receiving two reduced-intensity conditioning regimens for allogeneic transplantation: fludarabine and low-dose TBI (flu/TBI, n=25), or fludarabine, antithymocyte globulin and BU (flu/ATG/BU, n=41). The selection criteria were based on the hypothesis that flu/TBI patients were expected to achieve autologous recovery in the event of non-engraftment. Sixty-three patients (95%) engrafted. Regimen-related mortality at day 100 and 1 year was 6 and 15%, respectively. With median follow-up of 50.4 months, survival did not differ by regimen. Multivariate analysis confirmed that the type of regimen did not affect relapse. In patients achieving full donor chimerism by day 30, those conditioned with flu/TBI showed greater overall survival (P=0.02). Engraftment failure occurred in two patients (3%), both of whom received flu/TBI. We conclude that conditioning with flu/TBI or flu/ATG/BU yields comparable survival and remission outcomes. By contrast to our hypothesis, patients receiving flu/TBI who subsequently failed engraftment did not achieve autologous recovery. Yet, rapid attainment of full donor chimerism after flu/TBI is associated with greater survival than after flu/ATG/BU. Further, larger prospective randomized studies are required to define the advantage of one regimen over the other.

Six cases of permanent alopecia after various conditioning regimens commonly used in hematopoietic stem cell transplantation.

Alopecia, a side effect of chemotherapy, is usually temporary and reversible. Irreversible alopecia has been reported after high-dose chemotherapy (HDC) and hematopoietic stem cell transplantation (HSCT) especially related to BuCy containing conditioning regimens; however, the overall incidence is not known. We conducted a retrospective study to identify patients with chemotherapy-induced permanent alopecia after HSCT. We describe six such patients, two males and four females, among 760 patients transplanted between 1997 and 2004. Median age was 45 years (range, 37-65). There were three Caucasians and three African-Americans. Median follow-up was 30 months. Conditioning regimens included BuCy, Bu/Cy and etoposide (VP16) (one of these patients received second autograft after Cy and TBI) and CyVP16 and TBI. Our data show that permanent alopecia is a significant long-term side effect of HSCT and can be seen across the spectrum of diseases and transplant types and with non-busulfan containing regimens. We have observed that patients usually accept permanent alopecia as the price for the cure and therefore true incidence of permanent alopecia may be underestimated. Our findings may also have medico legal and psychosocial implications that need to be taken into consideration when consenting patients for HSCT.

Poor mobilization of peripheral blood stem cells is a risk factor for worse outcome in lymphoma patients undergoing autologous stem cell transplantation.

The effect of poor blood stem cells mobilization on the outcome of autologous stem cell transplantation (ASCT) has not been well studied. Our aim is to evaluate poor mobilization as a prognostic factor in lymphoma patients undergoing ASCT. We analyzed 90 consecutive patients with Hodgkin's (HD) and non-Hodgkin's lymphoma (NHL) who underwent ASCT. Poor mobilization was defined as the inability to obtain > or = 1 x 10(6) CD34+ cells/kg ideal body weight with two large volume aphereses. Patients were divided into 2 groups: group 1 = poor mobilizers, and group 2 = good mobilizers. The poor mobilizers received lower median transplant CD34+ cell dose (2 x 10(6) vs. 4.5 x 10(6)/kg for good mobilizers, P = 0.001), were more heavily pretreated (P = 0.01), and required higher number of aphereses for PBSC collection (P = 0.0006). The median progression-free survival (PFS) in groups 1 and 2 was 10 and 41 months (P = 0.04), while the median overall survival (OS) was 38 months and not reached (P = 0.02), respectively. Univariate analysis showed that > or = 3 pre-transplant treatments, CD34+ cell dose < or = 2 x 10(6), elevated LDH before transplant, and poor mobilization were significant prognostic factors for poor PFS, while only the first three were significant for worse OS. Multivariate analysis using these same four factors revealed that number of pre-transplant treatments (HR = 6.03, P = 0.001), CD34+ cell dose (HR = 0.1, P = 0.0007) were the only independent predictive factors for worse overall outcome. In conclusion, our data show that poor mobilization could indicate poor outcome in lymphoma patients undergoing ASCT, however, it is more likely to be a reflection of the heavy pre-transplant therapy and lower CD34+ cell dose re-infused in this group of patients.

Correlation of early lymphocyte recovery and progression-free survival after autologous stem-cell transplant in patients with Hodgkin's and non-Hodgkin's Lymphoma.

The importance of the association between early lymphocyte recovery and outcome has not been well studied in autologous stem cell transplantation (ASCT). In this retrospective study, we analyzed 90 consecutive patients with non-Hodgkin's and Hodgkin's lymphoma who underwent ASCT. Patients were divided into two groups: group 1 with absolute lymphocyte count (ALC) on day +15 below the median of 667/mm(3), and group 2 with ALC >or=667/mm(3). The median progression-free survival (PFS), but not overall survival (OS), was significantly longer in group 2 when compared to group 1 (16 months vs not reached P=0.02). Group 2 patients also had significantly shorter hospital stay, received higher CD34(+) cell dose, and had shorter time to neutrophil recovery. Multivariate analysis demonstrated day +15 ALC to be an independent prognostic indicator for PFS, but not OS, while CD34(+) cell dose and the number of pretransplant treatments were better predictors for both PFS and OS. We conclude that higher day +15 ALC may independently predict better PFS after ASCT for lymphoma patients; however, whether this merely reflects faster overall recovery caused by higher infused CD34(+) cell dose and less pretransplant therapy needs further investigation.

Treatment of refractory acute leukemia with timed sequential chemotherapy using topotecan followed by etoposide + mitoxantrone (T-EM) and correlation with topoisomerase II levels.

A phase I/II clinical study evaluated 17 patients with refractory/recurrent acute leukemia treated with 1.5 mg/m2/day topotecan on days 1-3 followed by etoposide (100 mg/m2/day)+mitoxantrone (10 mg/m2/day) on days 4, 5 and 9, 10. Timed sequential chemotherapy using the topoisomerase I-inhibitor topotecan before the topoisomerase II-inhibitors, etoposide+mitoxantrone (T-EM) treatment is proposed to induce topoisomerase II protein levels and potentiate the cytotoxic activity of the topoisomerase II-directed drugs. Fourteen patients had refractory and three had recurrent acute leukemia. The majority of patients were heavily pre-treated with greater than three re-induction chemotherapy regimens. Ten patients responded to T-EM treatment (59%). Four of seventeen (24%) had a complete remission and one had a partial remission. Four additional patients (24%) who scored complete leukemia clearance had no evidence of disease with complete white and red blood cell recovery but with platelet counts less than 100,000. The lack of platelet recovery in one patient having a partial response was scored as a partial leukemia clearance. The toxicity profile included major non-hematological toxicity including grade 3 mucositis (29%) and neutropenic fever (65%). Paired measurements of intracellular levels of topoisomerase II isoforms alpha and beta in leukemia blast cells (bone marrow) collected before (day 0) and after topotecan treatment (day 4) showed that a relative increase of topoisomerase IIalpha (Topo IIalpha) > or = 40% strongly correlated with response after T-EM treatment. Increased Topo IIalpha levels also corresponded to increased DNA fragmentation. Two patients who had an increase of Topo IIalpha of 20-25% had either a PR or PLC while patients with a < 10% increase showed no response to T-EM treatment. We conclude that timed sequential chemotherapy using topotecan followed by etoposide+mitoxantrone is an effective regimen for patients with refractory acute leukemia, and demonstrate Topo IIalpha protein level increases after topotecan treatment.

Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital.

Despite new antifungal treatment strategies, invasive aspergillosis (IA) remains a principal cause of infectious mortality after bone marrow transplantation (BMT). We reviewed the medical records of 93 allogeneic and 149 autologous transplant recipients during a 20 month period, with attention to cases of proven or probable IA. No autologous transplant recipient developed IA, whereas IA was seen in 15.1% of allogeneic recipients (including two of five patients with a prior history of IA despite prophylaxis), for an overall incidence of 5.8%. The median time to occurrence was 92 days post transplant, with no de novo cases developing prior to engraftment. Survival 100 days from diagnosis was 29%. Risk factors for the development of IA included > or = 21 days of corticosteroid therapy of >or= 1mg/kg/day and post-transplant cytomegalovirus (CMV) infection. These two risk factors were statistically linked. Our data illustrate a shift toward a later occurrence of post-transplant IA, suggesting a need for close, prolonged surveillance in the outpatient environment. The contributory role of protracted corticosteroid use is also highlighted. These data have important implications in an era of alternate donor transplants and more intense immunosuppression. Established strategies implementing newer, less toxic antifungal agents as prophylaxis in high-risk patients are needed.

Engraftment syndrome in breast cancer patients after stem cell transplantation is associated with poor long-term survival.

An autoaggression graft-versus-host (GVHD)-like syndrome or engraftment syndrome (ES) presenting with skin rash, fever, and other clinical findings can accompany the early phase of engraftment after autologous peripheral blood stem cell (PBSC)/bone marrow (BM) transplantation. Because ES was suggested to be analogous to GVHD, we have investigated whether ES was associated with any graft-versus-tumor effect that would affect disease progression and survival in breast cancer patients. Eighty-five consecutive patients who received BM/PBSC transplantation for breast cancer (stages II-IV) between July 1991 and July 1997 with minimum 2-year follow-up were studied. Median follow-up time was 892 days (range, 106-2913 days). Thirty-three patients (39%) developed ES. The incidence of relapse/progressive disease for the whole cohort was 61% and was similar in patients who developed ES compared with those who did not. However, there was an increased rate of mortality observed among the patients who had developed ES versus those who had not, although it was statistically not significant, (52% versus 31%, respectively; log rank, P = .08). Increased mortality rates due to disease progression were seen in all patients with ES regardless of their disease stage. In relapsed patients, median survival time after transplantation was 586 days for those with ES versus 847 days for those without ES, and the mortality rate was 85% (17/20) versus 51% (16/31) (P = .008) for those with or without ES, respectively. Visceral (lung, liver, brain, adrenal) or multiple-site relapses were observed in 85% of patients with ES versus 52% without ES (P = .01). In conclusion, whereas there was no effect of ES on relapse rate, a surprisingly significant increase in disease-related mortality rates among relapsed breast cancer patients with ES was found. Thus, patients with ES should be considered for close follow-up and further therapy posttransplantation.

Gastroparesis following bone marrow transplantation.

Patients often develop nausea, vomiting and bloating after bone marrow transplantation (BMT). These symptoms may interfere with nutrition and the ability to take oral medications. Gastroparesis is a recognized cause of these symptoms in non-transplant patients but less is known about patients who undergo BMT. Between January 1996 and March 1997, a total of 151 patients underwent BMT. Eighteen patients (12%) developed persistent symptoms suggestive of gastroparesis (persistent nausea, vomiting or bloating). Scintigraphic gastric emptying studies were performed to assess for gastroparesis. Prokinetic agents were administered at the time of study. The records on these patients were compared with those of all other patients undergoing BMT during the same time period without these symptoms. Nine patients who demonstrated delayed gastric emptying were further evaluated with esophagastroduodenoscopy and biopsy. Biopsy samples were reviewed for evidence of graft-versus-host disease (GVHD). Fourteen of 18 patients demonstrated delayed gastric emptying and most responded to prokinetic agents given at the time of study. Age, conditioning regimen, cytomegalovirus antigenemia and acute GVHD did not appear to be associated with the development of gastroparesis. Allogeneic BMT recipients were at higher risk than autologous BMT patients (26% vs 0%, P < 0.0001). of allogeneic bmt recipients, there was a nonsignificant trend of patients receiving tacrolimus to be less likely to experience gastroparesis than those receiving cyclosporine (27% vs 48%, P = 0.08). For the nine patients undergoing upper endoscopy, GVHD on gastric biopsy was an uncommon finding and was mild when present. Gastroparesis appears to be a common cause of nausea, vomiting and bloating following allogeneic BMT. This may occur less often with tacrolimus than cyclosporine because of the former agent's prokinetic properties. Patients usually respond to prokinetic drugs at the time of scintigraphy. GVHD and CMV infection do not appear to be major contributing factors.

Expression of antisense RNA to aldehyde dehydrogenase class-1 sensitizes tumor cells to 4-hydroperoxycyclophosphamide in vitro.

Previous studies in this laboratory showed that the overexpression of human aldehyde dehydrogenase class-1 (ALDH-1) with a retroviral vector resulted in increased resistance to 4-hydroperoxycyclophosphamide (4-HC), an active metabolite of cyclophosphamide. The present study examined the effect of ALDH-1 antisense RNA expression on ALDH-1 activity and sensitivity to 4-HC toxicity. Three different ALDH-1 cDNAs were synthesized that are either missing the N terminus (N), C terminus (C), or both (NC) and subcloned into the BamHI cloning site of pLXSN retroviral vector in the antisense (AS) orientation (AS-N, AS-C, and AS-NC, respectively). It was demonstrated that the overexpression of each of the AS constructs in K562 leukemic cells and A549 lung cancer cells results in suppression of ALDH-1 mRNA and enzymatic activity. Furthermore, the AS-N and AS-NC were generally more effective than AS-C in reducing the ALDH-1 activity. Both K562 and A549 cells expressing the ALDH-1 AS became significantly more sensitive to 4-HC toxicity as demonstrated by clonogenic and liquid culture assays. The increase in 4-HC sensitivity was in correlation with the degree of suppression of ALDH-1 activity. Moreover, such increase in 4-HC sensitivity, especially with AS-N and AS-NC, was to a similar degree seen with the use of diethylaminobenzaldehyde, a specific inhibitor of ALDH-1. These results indicate that ALDH-1 expression and activity can be specifically and effectively suppressed by AS RNA and lead to increased sensitivity to 4-HC.

Characterization and outcome of "hard to mobilize"' lymphoma patients undergoing autologous stem cell transplantation.

A "hard to mobilize" patient was defined as one in whom >or= 1x10(6) CD 34+ cells/kg cannot be obtained after two consecutive large volume aphereses. Forty-four consecutive Hodgkin's and non-Hodgkin's lymphoma patients who underwent autologous peripheral blood stem cell (PBSC) transplant treatment between June 1996 and June 1998 were included in this study. Twenty-one patients (48%) met the definition of "hard to mobilize" (Group I). All the rest of the patients (n=23) were the good mobilizers (Group II). The initial mobilization protocol for most patients was 10 microg/kg of G-CSF alone for both groups. For Group I, 7/21 (33%) patients were unable to achieve a minimal dose of >or= 1x10(6) CD34+ cells/kg even after a second mobilization attempt and/or bone marrow (BM) harvest (n=5). Overall, 11/21 (52%) required an additional mobilization and/or BM harvest. Only 3/21 (14%) patients were able to meet the target cell dose of >or= 2.5x10(6) CD34+ cells/kg (median of 4 apheresis). In contrast, 87% of Group II achieved the target dose with a median of 2 aphereses. Predictors of poor mobilization were greater than two prior treatment regimens (p=0.038) and the WBC count (<25,000/microL) on the first day of apheresis (p=0.053). Nineteen patients in Group I and all Group II completed treatment with a median time to engraftment of ANC>500/microl of 12 and 11 days, and platelet >20x10(3)/microl of 31 and 13 days, respectively. Outcome analysis revealed that 6/19 patients in Group I died of relapse within one year from transplant compared with only 2/23 of Group II who died of relapse (p=0.005, log rank test). There were no treatment related deaths in either group. Independent predictive features for "hard to mobilize" patients are a lack of significant increase in WBC count on the first day of apheresis and the number of prior treatment regimens. Poor mobilization appears to predict a worse outcome after autografting for lymphoma patients.

Comparison of autologous peripheral blood stem cell dosing by ideal vs actual body weight.

In this retrospective study, we evaluated the predictability of PBSC dose for hematopoietic engraftment comparing that calculated by ideal body weight (IBW) vs another calculated by actual body weight (ABW) for each patient. Sixty-three consecutive patients treated similarly using one transplant protocol were analyzed. While all patients had data available on CFU-GM and nucleated cells (NC), data on CD34+ enumeration was present only in 34 patients. We found that 49% of the patients were greater than 25% over their IBW. In addition, least-squares linear regression was used to assess the strength of the linear relationship between the inverse of cell dose/kg of ABW or IBW and time to AGC or platelet engraftment and showed no difference in r2 values for platelet engraftment, while using dose/kg of IBW greatly improved the ability of NC (r2 improved from 0.19 for ABW to 0.35 for IBW) and CFU-GM (r2 improved from 0.35 for ABW to 0.53 for IBW) to predict time to AGC engraftment, but did not change the CD34 r2. Hazard ratios were estimated using Cox proportional hazards regression and in all instances were found greater than 1.0 indicating that the probability of engraftment increased as cell dose/kg ABW or IBW increased. Finally, our data showed that 10 patients (16%) could have had one less apheresis procedure performed to obtain their set target stem cell dose calculated per kg IBW rather than ABW. In conclusion, PBSC dose per kg IBW is as good or better predictor of engraftment of AGC and may lead to cost savings in a certain subset of patients.

Morbidity and mortality following bone marrow transplantation: predictive utility of pre-BMT affective functioning, compliance, and social support stability.

This study investigated the utility of 3 pretransplant psychological variables (affective functioning, compliance, social support stability) in predicting subsequent bone marrow transplantation (BMT) health outcomes. The pre-BMT psychological evaluations of 92 BMT recipients were coded along the specified psychological dimensions and used to predict post-BMT survival status and health-related quality of life. Data analyses showed that, in addition to medical risk status (low) and quality of the marrow graft (histocompatible), higher levels of pre-BMT affective functioning and social support stability significantly predicted survival status (i.e., alive) and higher levels of quality of life. These findings have important implications for the role of psychological assessment prior to BMT and the need for interventions designed to enhance psychological functioning and subsequent health outcomes following BMT.