Stratified Intense-Dose- Yttrium-90 Ibritumumab Tiuxetan (90YIT ) with Bendamustine+Fludarabine Nonmyeloablative Conditioning for Allogeneic Stem Cell Transplantation in b-Cell Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 662-662
Author(s):  
Issa F. Khouri ◽  
Bill Erwin ◽  
Alison M Gulbis ◽  
Francesco Turturro ◽  
S Cheenu Kappadath ◽  
...  
Keyword(s):  
Cord Blood ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Median Number ◽  
Whole Body ◽  
Fixed Dose ◽  
Patient Specific ◽  
Organ Doses ◽  
Significant Difference

Abstract Background: Nonmyeloablative allogeneic transplantation has the potential to induce long-term remissions in patients with relapsed lymphoma. However, a non-intense conditioning regimen enhances the risk of early relapse. Anti-CD20 antibody radioimmunotherapy (90YIT) delivers radiation dose not only to the tumor cells that bind the antibody but also to inaccessible neighboring cells as a result of the cross-fire effect. Thus, we hypothesized that the addition of escalated 90YIT dose to the recently published bendamustine+fludarabine conditioning regimen (Khouri et al. Blood 2014) would facilitate early cytoreduction in such patients and promote improved long-term disease control by the allogeneic graft. Organ doses from a 90YIT weight-based activity prescription (mCi/kg) vary considerably, which justifies a dosimetry-based strategy for mCi/kg escalation. Methods and patients: On days -22 and -14, rituximab was given at 250 mg/m2 preceding 111In ibritumumab and 90YIT administration, respectively. Organ dosimetric assessment was performed based on serial 111In ibritumumab whole body scanning (0, 4, 24, 72 and 144 hours) , to select from among five 90YIT mCi/kg prescriptions (0.5, 0.75, 1, 1.25 or 1.5) that would result in an estimated 10 - 12 Gy dose to the liver, lungs or kidneys. Organ dose was corrected for patient-specific mass, based on a CT volume estimate times 1.03 g/cc for liver and kidneys, and a variable specific gravity for lungs (Simon, J Clin Monit Comput, 2000). Bendamustine 130 mg/m2 plus 30 mg/m2 of fludarabine IV were given daily on days -5 to - 3 prior to transplantation. Tacrolimus and mini-methotrexate (Mycophenolate mofetil in case of cord blood transplantation) were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant. Results: Twenty patients were studied. The median age was 58 years (range, 37-71). Lymphoma histologies included: indolent (n=8, 40%), diffuse large cell (n=6; 30%), double-hit (n=2; 10%) and mantle cell (n= 4, 20%). The median number of prior chemotherapies received was 4 (range, 2-7). At study entry, 8 patients (40%) were in complete remission following salvage therapy, 7 (35%) were in partial response, and 5 (25%) had refractory disease. Six of 16 (37.5%) patients tested were PET+. Dosimetry: The most exposed organ was either liver (16 patients) or lungs (4 patients). The distribution among the five 90YIT mCi/kg prescriptions (smallest to largest) was 2, 4, 12, 1 and 1, with a mean of 0.94 ± 0.23 mCi/kg. If all twenty patients were treated at 1 mCi/kg (the most common prescription), the 20 Gy limit employed for 90YIT clinical trials prior to approval would have been exceeded in only one patient for the liver (22.9 Gy) or lungs (20.9 Gy). The maximum liver and lung doses at 0.75 mCi/kg would have been 17.2 and 15.7 Gy, respectively. Transplant outcomes: Fifteen patients (75%) received their transplants from unrelated donors (including 1 mismatched and 2 cord blood), and only 5 (25%) from HLA-compatible siblings. The median number of CD34+ cells infused was 6.2 × 106/kg. Neutrophil counts recovered to > 0.5 × 109/L after a median of 12 days (range, 0-24 days). Platelet counts recovered to > 20 × 109/L after a median of 19 days (range, 9-30 days). By day 30, median donor myeloid and T-cells were 100% (range, 98-100). The cumulative incidence of acute grade 2-4 GVHD and chronic extensive GVHD were 25% (5% for acute grade 3-4) and 32%, respectively. Treatment-related mortality (TRM) rates at day 100 and 1 year after transplantation were 0% and 10%, respectively. The 2 cord blood transplants engrafted with 100% donor cells and none had GVHD. With a median follow-up duration of 14 months (range, 3-34 months), the overall survival and progression-free survival rates were 85% and 70%, respectively. No significant difference in survival or TRM could be detected by age, donor type, histology, disease status, PET status or number of prior therapies. Conclusions: Our results indicate that dose-intense 90YIT combined with fludarabine and bendamustine is a well-tolerated nonmyeloablative allogeneic conditioning for lymphoid malignancies, with promising results of engraftment, GVHD and survival. Our stratified 90YIT prescription results suggest that future studies with a fixed dose of 1 mCi/kg level without dosimetry would have an acceptable radiation risk to vital organs in this setting. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

scholarly journals Addition of Bortezomib to High Dose Melphalan As Conditioning Regimen for Autologous Stem Cell Transplantation Improves the Response Rate in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4647-4647 ◽  
Author(s):  
Benedetta Dalla Palma ◽  
Lucia Prezioso ◽  
Fabrizio Accardi ◽  
Stefano Bisbano ◽  
Federica De Luca ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
High Dose Melphalan

Abstract High-dose Melphalan (HDM) is the most commonly used conditioning regimen for autologous stem cell transplantation (ASCT) in newly diagnosed transplant-eligible Multiple Myeloma (MM) patients. Recent evidence suggests that the depth of response after induction therapy influences progression free survival (PFS) and, in most studies, overall survival (OS). Actually the effect of the inclusion of new drugs in the conditioning regimen for ASCT is still unknown. Phase I-II clinical study showed that the addition of Bortezomib (Bor) to HDM is safe and a promising conditioning regimen. Thus, in this study we analyzed a single center experience on the use of Bor in combination with HDM (Bor-HDM) as conditioning regimen before ASCT as frontline treatment in MM patients in order to evaluate the safety and the response rates of this combination regimen. We analyzed a total cohort of 48 newly diagnosed MM patients (25 females and 23 males; median age 60 years, range 42-70) admitted consecutively to our Bone Marrow Transplantation Center from 2008 to 2014. Regarding prognostic stratification, 25% of patients were classified as stage III according to International Staging System (ISS), and 12% exhibited high-risk cytogenetic features (defined by presence of del(17p) and/or t(4;14) and/or t(14;16)). All patients with the exception of three underwent to 3-drugs Bor-based induction therapy including Bor (median cumulative dose: 28.9 mg/m2), Thalidomide and Dexamethasone (VTD). After induction therapy and stem cell collection 28 out of 48 patients were treated with Bor-HDM, whereas 20 patients with HDM alone as conditioning regimen before ASCT. HDM was administered on day -2 (median dose: 200 mg/m2), and a single-dose Bortezomib at the dosage of 1.3 mg/m2 was administered on day -1 in the Bor-HDM group. Stem cells were reinfused on day 0 (median number of CD34+ infused: 3.3x106/Kg, range 1.86-6x106/Kg). Responses were evaluated at day 100 after ASCT, and definitions of response were used according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for MM. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher's exact test. pvalue of <0.05 was considered significant. Any significant difference was not observed between Bor-HDM group vs HDM group, regarding age at diagnosis (p=0.77), sex (p=0.24), cumulative induction dose of Bortezomib (p=0.42), dose of Melphalan used for conditioning (p=0.16) and the median number of CD34+ cells infused (p=0.12). Distribution of ISS stage was similar in the two groups (p=0.14), as well as that of high-risk cytogenetic (p=0.14). Moreover the response rates after the induction therapy was not statistically different in the two groups of patients analyzed (sCR + CR: 19% in Bor-HDM group vs 26% in HDM group; VGPR: 33% vs 48%; PR: 48% vs 26%, p=0.22). Any significant difference on hematopoietic recovery rates was not observed in Bor-HDM as compared to HDM alone with a mean time to neutrophil recovery of 12 days (range 9-18) and to platelet recovery of 12 days (range 9-21) in both groups. Bor-HDM conditioning was well tolerated, without increase of neuropathy occurrence. Then we analyzed the response rate after ASCT, showing that the overall response rate (ORR) was significantly higher in Bor-HDM group as compared to HDM (sCR+CR: 56% in Bor-HDM vs 17% in HDM; VGPR 30% vs 28%; PR: 15% vs 56%, p=0.0072) with a higher number of "good quality" response (sCR + CR + VGPR: 86% vs 45%; p=0.0075). The number of sCR was also significantly higher in Bor-HDM as compared to HDM alone (23% vs 0%, p=0.067). Moreover an improvement of the response rate after ABMT was seen more frequently in the Bor-HDM group as compared to the HDM group (p=0.0063). We then observed that the number of patients that underwent tandem ASCT was higher in the HDM group (66% vs 41%), even not reaching a statistical significance. In conclusion, this retrospective analysis suggests that BOR-HDM is safe as conditioning regimen with a higher response rate after ASCT as compared to the standard HDM regimen giving the rational design for randomized studies needed to assess whether this conditioning regimen is superior to HDM alone. Disclosures Giuliani: Celgene: Research Funding; Janssen: Research Funding.

scholarly journals The Long-Term Follow-Up of Patients with Cystine Stones: A Single-Center Experience for 13 Years

2021 ◽  
Vol 10 (7) ◽  
pp. 1336
Author(s):  
Toshifumi Takahashi ◽  
Shinya Somiya ◽  
Katsuhiro Ito ◽  
Toru Kanno ◽  
Yoshihito Higashi ◽  
...  
Keyword(s):  
Surgical Intervention ◽  
Median Number ◽  
Small Sample ◽  
Age At Diagnosis ◽  
Surgical Interventions ◽  
Significant Difference ◽  
Long Term Follow Up ◽  
Cystine Stones

Introduction: Cystine stone development is relatively uncommon among patients with urolithiasis, and most studies have reported only on small sample sizes and short follow-up periods. We evaluated clinical courses and treatment outcomes of patients with cystine stones with long-term follow-up at our center. Methods: We retrospectively analyzed 22 patients diagnosed with cystine stones between January 1989 and May 2019. Results: The median follow-up was 160 (range 6–340) months, and the median patient age at diagnosis was 46 (range 12–82) years. All patients underwent surgical interventions at the first visit (4 extracorporeal shockwave lithotripsy, 5 ureteroscopy, and 13 percutaneous nephrolithotripsy). The median number of stone events and surgical interventions per year was 0.45 (range 0–2.6) and 0.19 (range 0–1.3) after initial surgical intervention. The median time to stone events and surgical intervention was 2 years and 3.25 years, respectively. There was a significant difference in time to stone events and second surgical intervention when patients were divided at 50 years of age at diagnosis (p = 0.02, 0.04, respectively). Conclusions: Only age at a diagnosis under 50 was significantly associated with recurrent stone events and intervention. Adequate follow-up and treatment are needed to manage patients with cystine stones safely.

scholarly journals Transitional Cell Carcinomas of the Urinary Tract in a Colony of Beagle Dogs

1989 ◽  
Vol 26 (6) ◽  
pp. 455-461 ◽  
Author(s):  
K. J. Nikula ◽  
S. A. Benjamin ◽  
G. M. Angleton ◽  
A. C. Lee
Keyword(s):  
Urinary Tract ◽  
Transitional Cell ◽  
Clinical Signs ◽  
Conclusive Evidence ◽  
Whole Body ◽  
Beagle Dogs ◽  
Long Term Effects ◽  
Significant Difference ◽  
Microscopic Features

Gross and light microscopic features of transitional cell carcinomas (TCC) of the urinary tract were examined in Beagle dogs used for the study of the long-term effects of low-dose, whole-body, 60Co gamma radiation. Thirty-eight cases of TCC occurred among 990 dogs that were from 0 to 14 years of age. There was no conclusive evidence of a radiation effect. The 38 TCC were equally divided between male and female dogs, but there was a significant difference in the sex distribution of urethra-origin TCC. Eleven males had a primary urethral TCC compared to only two females. There was no significant difference between the urethra-origin and bladder-origin TCCs in the number of tumors that caused clinical signs, metastasized, or that contributed to the death of the dog. All cases of urethral TCC in male dogs occurred in the prostatic urethra. The majority of these cases were not recognized to be neoplasms at gross necropsy, but microscopic examination revealed the TCC. Our findings differ from previous reports stating that TCC occurs more frequently in female than male dogs, and they especially differ from reports claiming that urethra-origin TCC is predominately a disease of female dogs.

scholarly journals Impact of Induction Treatment on Stem Cell Collection: A COVID Related Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4848-4848
Author(s):  
Brad Rybinski ◽  
Ashraf Z. Badros ◽  
Aaron P. Rapoport ◽  
Mehmet Hakan Kocoglu
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Research Funding ◽  
Median Number ◽  
Cell Transplant ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Number Of Cycles ◽  
Time Required ◽  
Stem Cell Collection

Abstract Introduction: Standard induction therapy for multiple myeloma consists of 3-6 cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide and dexamethasone (KRd). Receiving greater than 6 cycles of a lenalidomide containing regimen is thought to negatively impact the ability to collect sufficient CD34+ stem cells for autologous stem cell transplant (Kumar, Dispenzieri et al. 2007, Bhutani, Zonder et al. 2013). Due to the COVID-19 pandemic, at least 20 patients at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCC) had transplant postponed, potentially resulting in prolonged exposure to lenalidomide containing induction regimens. Here, in the context of modern stem cell mobilization methods, we describe a retrospective study that suggests prolonged induction does not inhibit adequate stem cell collection for transplant. Methods: By chart review, we identified 56 patients with multiple myeloma who received induction with VRd or KRd and underwent apheresis or stem cell transplant at UMGCC between 10/1/19 and 10/1/20. Patients were excluded if they received more than 2 cycles of a different induction regimen, had a past medical history of an inborn hematological disorder, or participated in a clinical trial of novel stem cell mobilization therapy. We defined 1 cycle of VRd or KRd as 1 cycle of "lenalidomide containing regimen". In accordance with routine clinical practice, we defined standard induction as having received 3-6 cycles of lenalidomide containing regimen and prolonged induction as having received 7 or more cycles. Results: 29 patients received standard induction (Standard induction cohort) and 27 received prolonged induction (Prolonged induction cohort) with lenalidomide containing regimens. The median number of cycles received by the Standard cohort was 6 (range 4-6), and the median number of cycles received by the Prolonged cohort was 8 (range 7-13). The frequency of KRd use was similar between patients who received standard induction and prolonged induction (27.58% vs. 25.93%, respectively). Standard induction and Prolonged induction cohorts were similar with respect to clinical characteristics (Fig 1), as well as the mobilization regimen used for stem cell collection (p = 0.6829). 55/56 patients collected sufficient stem cells for 1 transplant (≥ 4 x 10 6 CD34 cells/kg), and 40/56 patients collected sufficient cells for 2 transplants (≥ 8 x 10 6 CD34 cells/kg). There was no significant difference in the total CD34+ stem cells collected at completion of apheresis between standard and prolonged induction (10.41 and 10.45 x 10 6 CD34 cells/kg, respectively, p = 0.968, Fig 2). Furthermore, there was no significant correlation between the number of cycles of lenalidomide containing regimen a patient received and total CD34+ cells collected (R 2 = 0.0073, p = 0.5324). Although prolonged induction did not affect final stem yield, prolonged induction could increase the apheresis time required for adequate collection or result in more frequent need for plerixafor rescue. There was no significant difference in the total number of stem cells collected after day 1 of apheresis between patients who received standard or prolonged induction (8.72 vs. 7.96 x 10 6 cells/kg, respectively, p = 0.557). However, patients who received prolonged induction were more likely to require 2 days of apheresis (44% vs. 25%, p = 0.1625) and there was a trend toward significance in which patients who received prolonged induction underwent apheresis longer than patients who received standard induction (468 vs 382 minutes, respectively, p = 0.0928, Fig 3). In addition, longer apheresis time was associated with more cycles of lenalidomide containing regimen, which neared statistical significance (R 2 = 0.0624, p = 0.0658, Fig 4). There was no significant difference between standard and prolonged induction with respect to the frequency of plerixafor rescue. Conclusions: Prolonged induction with lenalidomide containing regimens does not impair adequate stem cell collection for autologous transplant. Prolonged induction may increase the apheresis time required to collect sufficient stem cells for transplant, but ultimately clinicians should be re-assured that extending induction when necessary is not likely to increase the risk of collection failure. Figure 1 Figure 1. Disclosures Badros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

scholarly journals Effects of low dose radiation on immune cells subsets and cytokines in mice

2020 ◽  
Vol 9 (3) ◽  
pp. 249-262
Author(s):  
Xiaochang Liu ◽  
Zheng Liu ◽  
Duo Wang ◽  
Yang Han ◽  
Sai Hu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Low Dose ◽  
White Blood Cells ◽  
Whole Body ◽  
Low Dose Radiation ◽  
Dose Irradiation ◽  
Significant Difference ◽  
Dose Radiation

Abstract Whole-body exposure to low-dose radiation due to diagnostic imaging procedures, occupational hazards and radiation accidents is a source of concern. In this study, we analyzed the effects of single and long-term low-dose irradiation on the immune system. Male Balb/c mice received a single whole-body dose of irradiation (0.01, 0.05, 0.2, 0.5 or 1 Gy). For long-term irradiation, mice were irradiated 10 times (total dose of 0.2, 0.5 or 1 Gy) over a period of 6 weeks. Two days after single or long-term irradiation, the numbers of splenic macrophages, natural killer cells and dendritic cells were reduced, and the spleen organ coefficient was decreased. At 2 Days after long-term low-dose irradiation, the number of white blood cells in the peripheral blood of the mice decreased. Between 7 and 14 Days after long-term low-dose irradiation, the number of immune cells in the thymus and spleen began to increase and then stabilized. Th1/Th2 cytokines and reactive oxygen species-related proteins first decreased and then increased to a plateau. Our results show a significant difference in the effects of single and long-term low-dose irradiation on the immune system.

A Profile of 44 Long Term Survivors (>10yrs) with AL Amyloidosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4765-4765
Author(s):  
Ashutosh D. Wechalekar ◽  
Helen J. Lachmann ◽  
Julian D. Gillmore ◽  
Philip N. Hawkins
Keyword(s):  
Soft Tissues ◽  
Performance Status ◽  
Organ Involvement ◽  
Whole Body ◽  
Al Amyloidosis ◽  
Term Survival ◽  
Long Term Outcome ◽  
Significant Difference ◽  
Amyloid Load

Abstract AL amyloidosis has a poor outcome. Survival of only about one year was frequently reported in studies performed in the 1990s, and the diagnosis of AL amyloidosis continues to be widely regarded as incompatible with long term survival. We report here the features of patients with AL amyloidosis followed up at the UK Amyloidosis centre (NAC) for more than 10 years, who encouragingly represented more than 10% of all cases. All patients with AL amyloidosis who first attended the NAC between 1979–1997 and subsequently survived for more than 10 years were included in this study. AL type amyloidosis was confirmed in all patients histologically with genetic studies to robustly exclude hereditary amyloidosis as indicated. Organ involvement and responses were defined as per the international consensus criteria (Gertz et al 2005). I123 serum amyloid P (SAP) scintigraphy was used to identify additional organ involvement and monitor amyloid load. 361 patients with AL amyloidosis were assessed at the NAC before 1st August 1997, with a median survival of 2.4 yrs. 132 (20%) patients survived >5 yrs, and 44 (12%) patients survived >10 years with 2 patients living ≥ 16 yrs and 7 for ≥ 14 yrs. Three patients died at 10.2, 11 and 13 years due to unrelated causes with no deaths due to progressive amyloidosis. Among the 44 ten year survivors, at presentation, median age was 51 yrs (29–70), median creatinine 86μmol/L (47–400), 24 hour proteinuria 2g (<0.1g–50g), bilirubin 8μmol/L (2–130), alkaline phosphatase 82.5 units/L (41–2645), and median NT-ProBNP 19 pMol/L (1–2158). Median ECOG performance status was 1 (0–2). Organ involvement (consensus criteria) was: renal 31 (70%); liver 6 (14%); cardiac 8 (18%); autonomic neuropathy 1(2%); peripheral neuropathy - none; gastrointestinal 2(4%) and lymph nodes or other soft tissues 4 (9%). SAP scintigraphy showed renal amyloid deposits in 30 (68%), liver 11(25%), adrenals 3(7%) and bone infiltration 7 (16%). 35 (79%) had one organ involved, 8 (18%) had 2 organs and 1 (3%) patient had three organs involved by consensus criteria; SAP scintigraphy detected additional organ involvement in 12 cases (27%). The whole body amyloid load on SAP scintigraphy was small in 25(57%), moderate 2 (4%) and large 9 (21%). Median plasma cell infiltrate in the marrow was 5% (1–65). Treatment received comprised an alkylator based regimen in 11(26%), VAD chemotherapy in 14 (32%), and stem cell transplantation (SCT) in 18 (42%). 29 (67%) patients had a complete clonal response, 13 (30%) had a partial response and 1 (2%) had no response. 25(57%) had evidence of organ improvement by conventional criteria and in 26 (59%) SAP scintigraphy showed regression of amyloid. The median time to next treatment (progression free survival - PFS) has not been reached at 10 yrs. There was no significant difference in the PFS between patients treated chemotherapy or SCT, or among the complete or partial responders. 13 patients (30%) developed end stage renal disease (ESRD) a median 5.8 yrs after diagnosis and this was not significantly more frequent among partial responders compared with complete hematologic responders. Substantial improvements in diagnosis, monitoring and treatment of AL amyloidosis have occured since 1997. It is all the more encouraging that we are able to report here that 12% of patients diagnosed before this time survived for more than 10 years and patients with AL amyloidosis diagnosed more recently are likely to have even better prospect of good long term outcome in cases who achieve good and sustained clonal responses to therapy.

Allogeneic Hematopoietic Cell Transplantation From Combined Haploidentical Family Members and Unrelated Cord Blood (CB) Can Benefit High Risk Patients Lacking HLA-Identical Donors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3378-3378 ◽  
Author(s):  
Elizabeth Shima Rich ◽  
Andrew Artz ◽  
Theodore Karrison ◽  
Lucy A Godley ◽  
Olatoyosi Odenike ◽  
...  
Keyword(s):  
High Risk ◽  
Cord Blood ◽  
Median Time ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Bone Marrow Cells ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Blood Transplantation

Abstract Abstract 3378 Poster Board III-266 Introduction: Haploidentical-cord blood transplantation is a promising approach for patients (pts) who lack HLA donors and may improve rates of early engraftment while allowing long term cord blood reconstitution with low rates of GVHD. We enrolled 29 pts (17 AML/MDS, 4 ALL, 3 CML, 4 NHL/HL, 1 severe aplastic anemia) lacking HLA identical donors. The median age was 40 years (range, 4-67), and median weight was 75 kg (range, 14-125). Twenty-two (76%) pts had active disease at time of transplant; 6 had prior autologous transplants. 14 pts were Caucasian; 15 were other race or ethnicity. The haploidentical donor was the mother in 4; father in 3; child in 10; sibling in 10; and half-sibling in 2 cases. The median haploidentical CD34+ dose was 2.51 × 106/kg (range, 1.25-10.95); CD3+ cells were 1.0 × 104/kg (range, 0.3-3.7). Single unrelated CB units were matched by low resolution at HLA-A and B and high-resolution at DRB1, and matched 6/6 in 2 pts; 5/6 in 18 pts; 4/6 in 9 pts. Median cord total nucleated cells equaled 1.93 × 107/kg (range, 1.07-9.36); CD34+ cells were 0.08 × 106/kg (range, 0.03-0.75). The conditioning regimen for 18 pts was fludarabine (Flu) (30 mg/m2 on d-7 through -3), melphalan (Mel) (70 mg/m2 on d -3 and -2), and Thymoglobulin (rATG) (1.5 mg/kg on d-7, -5, -3, -1). Eleven pts received Flu, thiotepa (5 mg/kg on d -7 and -6), total-body irradiation (TBI) (12 Gy lateral opposed fields in 2 Gy fractions BID on d-3 through -1), and rATG. GVHD prophylaxis consisted of tacrolimus (Tac) + methylprednisolone or Tac + mycophenolate. Engraftment: Two pts died early (sepsis, CVA). Three other pts failed to engraft with either haploidentical or CB and died of infection on d36, 43, and 63. One of these had anti-donor HLA antibodies. 24 pts engrafted with a median time to ANC >500/mL of 10 days (range, 9-31) and median time to sustained platelets >20,000/mL of 20 days (range, 15-63). In the majority of pts, early haploidentical engraftment was replaced by durable engraftment of CB by 100 days. However, 3 pts had persistent hematopoiesis associated with only the haploidentical donor, while a fourth pt engrafted with only CB on day 31. Late graft failure and death from sepsis occurred in one of the patients with haploidentical engraftment. In unfractionated peripheral blood or bone marrow cells, median haploidentical chimerism was 95% (range, 0-100) on d14; 76% (range, 0-95) on d30; 6% (range, 0-87) on d100. Median unfractionated cord chimerism was <5% (range, 0-100) on d14; 20% (range, 0-100) on d30; 85% (range, 0-100) on d100. In the CD3+ compartment, median haploidentical chimerism was 95% (range, 0-100) on d14; 86% (range, 0-95) on d30; 6% (range, 0-79) on d100. Median CD3+ cord chimerism was 5% (range, 0-100) on d14; 26% (range, 0-100) on d30; 90% (range, 1-100) on d100. Toxicities and outcome: Other fatal toxicities included VOD (1), EBV-associated PTLD (1), ARDS (1), cardiac arrest (1), intractable seizures (1). Two patients developed TTP and later died of complications related to sepsis. Five pts relapsed of whom 4 have died. Acute GVHD (aGVHD) grade II occurred in 3 pts, one of whom developed the only case of chronic GVHD after failing to continue prograf. No aGVHD grade III-IV was seen. Twelve pts are currently alive; 11 are without disease. The median follow up for survivors is 186 days (range, 16-642). Estimated one year survival is 26% (95%CI, 6-46), and PFS is 19% (1-36). Conclusions: Combined haploidentical and CB transplantation results in early haploidentical engraftment followed by durable CB predominance in a majority of pts. The median times to neutrophil engraftment are considerably shorter - and the range narrower - than with other methods of cord blood transplantation. Early haploidentical engraftment failed in four patients; cord blood engraftment also failed in three of these pts and in three others. Rates of acute and particularly of chronic GVHD are low. Durable remissions can be achieved even in high risk pts regardless of age or remission status at the time of transplant. Disclosures: Rich: Genzyme: Research Funding. Odenike:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. van Besien:Genzyme: Research Funding.

Contrasting the Long-Term Outcome of Reduced-Intensity Allogeneic Stem Cell Transplantation From Related Matched and Mismatched or Unrelated Matched Donor

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2029-2029
Author(s):  
Hui-Sheng Ai ◽  
Xiao-Jun Huang ◽  
Zhen-Hua Qiao ◽  
Jian-Min Wang ◽  
Ying-Min Liang ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Long Term Outcome ◽  
Hematological Diseases ◽  
Matched Group ◽  
Significant Difference ◽  
Reduced Intensity

Abstract Abstract 2029 Reduced-intensity conditioning (RIC) transplantation has been widely used in the treatment of hematological diseases. However, the comparison of long-term outcomes of RIC with HLA-matched, HLA–mismatched and unrelated donor is still lacking. Here, we reported the results of hematological patients treated at the China RIC Cooperative from the HLA-matched, HLA–mismatched and unrelated donor following to RIC. 514 patients with hematological diseases from the China RIC Cooperative Group were enrolled in this study, including 370 in HLA-matched group, 96 in HLA-mismatched group and 48 in unrelated group (table 1). The RIC conditioning regimen was based on fludarabine in combination with antilymphocyte globulin or busulfan or others. The graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A, mycophenolate mofetil and methotrexat. Results showed that 505 patients achieved stable donor chimerism. The incidence of II-IV aGVHD in the HLA-mismatched group was 42.7%, significantly higher than that in the HLA-matched group (21.4%) and the unrelated group (20.8%). The 100-day transplantation-related mortality was 30.2%, 14.5% and 4.2% in the three groups, respectively. The median follow-up time was 57 months (range,7 to 141 months). The overall relapse incidence was 14.8%, including 15.7% in the HLA-matched group, 14.6% in the HLA-mismatched group and 8.3% in the unrelated group. There was no significant difference in relapse incidences in the patients with AL-CR1 and CML-CP (16.4% and 11.2%), as well between the HLA-matched group (16.9% and 16.7%) and the unrelated group (11.1% and 8.8%). For the patients with advanced leukemia, a significantly lower relapse rate was found in the HLA-mismatched group in comparison with that in the HLA-matched group (18% vs 36.2%, p<0.05, Fig. 1).The Kaplan-Meier estimated DFS and OS at 6 years for all of the 514 patients were 58.6% and 61.9% respectively, and those at 11 years were 57.8% and 61.7% respectively. The DFS and OS at 6 years in the HLA-mismatched group was 35.4% and 38.5% respectively, lower than those at 11 years in the HLA-matched group (62.7% and 67.0%, p<0.01) and those at 6 years in the unrelated group (64.6% and 66.7%, p<0.01, Figure 2 A, B). The 11-year DFS for the patients with AL-CR1, CML-CP and MDS/SAA was 68.7%, 68.5% and 73.6% respectively in the HLA-matched group. The 6-year DFS for the patients with AL-CR1, CML-CP and MDS/SAA was 55.6%, 70.7% and 62% respectively in the unrelated group, and 37.5%, 62.5% and28.6% respectively in the HLA-mismatched group. Figure 2 C,D,E£© However, the 6-year DFS in the patients with advanced leukemia was 32.0% in the HLA-matched related group, similar to that in the HLA-mismatched group (31.9%, p£¾0.05, Fig. Figure 2 F). These results indicate that RIC transplantation had similar outcome in the HLA-matched group and unrelated group but better than that from the HLA-mismatched group in haematology diseases. However, for the advanced leukemia patients, the HLA-mismatched transplantation had much lower leukemia relapse rate than in the HLA-matched group. Fig 1: The relapse rate of the patients with advanced leukemia in the HLA-mismatched group and the HLA-matched group. Disclosures: No relevant conflicts of interest to declare.

Impact of Molecular Mutations on Treatment Response to Hypomethylating Agents in MDS

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 461-461 ◽  
Author(s):  
Fabiola Traina ◽  
Anna M Jankowska ◽  
Valeria Visconte ◽  
Yuka Sugimoto ◽  
Hadrian Szpurka ◽  
...  
Keyword(s):  
Treatment Response ◽  
Predictive Value ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Median Number ◽  
Categorical Variables ◽  
Hypomethylating Agents ◽  
Significant Difference

Abstract Abstract 461 Aberrant DNA methylation is a hallmark of myelodysplastic syndromes (MDS), MDS/myeloproliferative neoplasms (MDS/MPN) and secondary acute myeloid leukemia (sAML). It provides a rationale for treating these malignancies with hypomethylating agents like 5-azacitidine (AZA) and decitabine (DAC). However, treatment outcomes remain limited and heavily weighed on morphologic/cytogenetic results. The discovery of novel mutations has provided important insight into the pathogenesis of MDS and related disorders. Genes implicated in epigenetic regulation, including DNMT3A, TET2, IDH1/IDH2, EZH2, ASXL1 and UTX have been found mutated in MDS, while others have also been implicated in MDS pathogenesis. There is limited data on the predictive value of these genetic defects for treatment response and disease outcome. We hypothesized that these defects are important biomarkers predictive of response to hypomethylating agents. We studied 88 patients with MDS (RCUD=2, RARS=6, RCMD=11, MDS-U=3, RAEB-1/2=29, CMML1/2=16, MDS/MPN-U=5, RARS-T=5, AML from MDS=11) who received hypomethylating agents (AZA=53, DAC=24, both=11). The median number of cycles was 7 [range 1–35], median age was 69 years (range 42–82) and median follow-up was 18 months (range 0–76). Responses were scored according to IWG criteria. DNMT3A, TET2, IDH1/2, EZH2, ASXL1, UTX, KRAS, NRAS, CBL, RUNX1, TP53 and SF3B1 were sequenced using standard techniques. Categorical variables were analyzed using Chi-square statistics. Overall survival (OS) was analyzed using Kaplan-Meier; p-values ≤ 0.05 were considered statistically significant. Mutated patients were older than wild type (WT) cases (72 vs. 68 years, p=.01) but were well matched for marrow blast %, cytogenetic risk group and cycles of hypomethylating agents received. We found mutations in 40/88 (45%) patients. Mutations were most frequent in SF3B1 (6/11; 55%), ASXL1 (13/50; 26%), TET2 (18/88; 20%), KRAS (3/34; 9%), and DNMT3A (7/88; 8%). Less common were mutations in EZH2 (2/43; 5%), TP53 (1/23; 4%), IDH1 (4/88; 5%), IDH2 (3/88; 3%), and UTX (1/36;3%). No mutations were found in CBL, NRAS or RUNX1. Based on single mutations, overall response rate (ORR) was higher in mutated vs WT patients for DNMT3A (6/7 [86%] vs 33/81 [41%]; p=.02), ASXL1 (11/13 [85%] vs 14/37 [38%]; p=.003), and TET2 (12/18 [67%] vs. 27/70 [39%]; p=.03). All heterozygous DNMT3A mutants responded to hypomethylating agents. Differences remained significant when stratified to AZA treatment alone for DNMT3A (6/7 [86%] vs 21/56 [38%]; p=.01) and ASXL1 (9/11 [82%] vs 12/29 [41%]; p=.02) but not TET2 (6/10 [60%] vs 21/53 [40%]; p=0.22). The predictive value of combined mutations were analyzed for DNMT3A, TET2 and/or IDH1/2, showing better response to hypomethylating therapy in patients who had a mutation; ORR (mutated: 18/28 (64%) vs WT: 21/60 (35%); p=.01). This difference remained significant in patients receiving only AZA (n=53); ORR was 11/18 (61%) in mutant and 11/35 (31%) in WT patients (p=.03). No differences in ORR were noted for KRAS, EZH2 and IDH1/2 mutant and WT patients. No SF3B1 mutants responded to treatment while both patients with UTX and TP53 mutations responded. The frequency of AML evolution was also analyzed and showed no difference between mutant and WT cases for TET2 (7/18 [39%] vs 22/70 [31%];p=.52), ASXL1 (4/10 [40%] vs 11/35 [31%]; p=.61), and DNMT3A (3/7 [43%] vs 26/81 [32%];p=.56). No differences in OS and progression free survival (PFS) were noted between responders and non-responders to hypomethylating therapy (28 vs 17 mos, p=.25; 16 vs 8 mos, p=.54). Comparison of survival outcomes for mutant and WT patients showed no significant difference for DNMT3A (OS: 30 vs 21 mos, p=0.43; PFS: 20 vs 11, p=.53), ASXL1 (OS: 28 vs 22, p=.68; PFS: 16 vs 10, p=.88), and TET2 (OS: 30 vs 20 mos, p=.30). PFS was better in TET2 mutants compared to WT (19 vs 9, p=.03). No survival differences were noted between mutant and WT cases who responded to hypomethylating agents for DNMT3A (OS: 25 vs 28,p=.84; PFS: 14 vs 16, p=.78), ASXL1 (OS: 10 vs 18, p=.48; PFS: 10 vs 6, p=.76) TET2 (OS: 27 vs 16, p=.79; PFS: 18 vs10, p=.19). In conclusion, DNMT3A, ASXL1 and TET2 mutations were independently associated with a better response to hypomethylating drugs. Moreover, combined mutations in DNMT3A/TET2/IDH1/IDH2 may influence the response to hypomethylating agents, especially AZA supporting its role as a predictive biomarker in MDS treatment. Disclosures: Maciejewski: Celgene and Eisai, NIH, AA&MDS Foundation: Research Funding. Tiu:MDS Foundation Young Investigator Award: Research Funding.

Intermittent Zolendronic Acid (ZA) for the Prevention of Osteoporosis After Allogeneic Hematopoietic Cell Transplantation (HCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1965-1965
Author(s):  
Parameswaran Hari ◽  
Todd E. Defor ◽  
David H. Vesole ◽  
Christopher Bredeson ◽  
Linda J Burns
Keyword(s):  
Lumbar Spine ◽  
High Risk ◽  
Bone Resorption ◽  
Bone Loss ◽  
Femoral Neck ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Serum Osteocalcin ◽  
Zolendronic Acid

Abstract Abstract 1965 Bone mineral density (BMD) loss, osteoporosis, and avascular necrosis (AVN) of bone are relatively common in long term survivors of HCT with up to one half of recipients suffering post HCT bone loss. We performed a multi center phase II randomized open label trial of intravenous zolendronic acid (ZA) to prevent BMD loss in recipients of allogeneic HCT with pre-existing osteopenia prior to HCT. Methods: Eligible adult (>18 years) patients had baseline pre-transplant osteopenia defined as a T-score < −1 SD and > −2.5 SD (WHO definifition) at either the lumbar (L) spine and/or the proximal femur at a pre HCT screening evaluation with a dual energy X-Ray absorptiometry (DEXA) scan. Patients were eligible irrespective of donor source, stem cell type, or conditioning regimen intensity. Patients with myeloma, baseline renal dysfunction or concomitant active dental or endocrine issues precluding the use of ZA were excluded. Subjects were allocated by block randomization stratified by center and type of conditioning (myeloablative vs. non-myeloablative) to the treatment or control arms. Both treatment and control groups received 1000 mg of calcium and 400 – 500 IU of vitamin D orally daily and were encouraged to remain active and refrain from tobacco smoking and alcohol. Additionally subjects randomized to the treatment arm received ZA 4 mg iv over 15 minutes within 28 days pre-HCT and at 3 and 6 months (mo) after HCT. Control subjects did not receive ZA or other additional therapy for bone strength. ZA dose was modified for post HCT renal dysfunction. Primary outcome measure was change in BMD from baseline to 12 mo after HCT. Serum osteocalcin, serum bone specific alkaline phophatase (BSAP), and urinary N telopeptide (UNTX) were measured at baseline and at 6 and 12 mo. Results: Between 2006 and 2010, 61 patients were randomized – 32 to the ZA treatment cohort and 29 to the control arm. Cohorts were balanced for age, sex, performance score, donor type, diagnoses and conditioning regimen intensity. HCT co-morbidity index (HCTCI) was significantly worse in the ZA arm (50% with high risk scores > 3). Baseline BMD, T scores at the femoral neck and lumbar spine, urinary NTX, serum osteocalcin and BSAP were similar in both cohorts. Differences between cohorts in bone density and bone specific laboratory parameters at 12 mo post HCT are summarized in Table 1. There was significant increase in BMD at the femoral neck and lumbar Spine; with concomitant decease in bone resorption markers for the treatment group (ZA cohort). Incidences of acute and chronic graft vs. host disease and relapse rates were similar between cohorts. There was significantly higher 1 year mortality in the ZA cohort (15 deaths vs. 6 in the control cohort). Thus overall survival was inferior in the ZA cohort 43% vs. 75% at 2 years post HCT. Grade 3–4 adverse events were similar. Conclusions: We randomized HCT recipients at high risk of post transplant bone loss to receive 3 doses ZA starting prior to HCT. ZA prevented further bone loss and resulted in improvement in BMD and T scores as well the bone resorption marker, urinary NTX. Lower survival was observed in the ZA cohort likely related to baseline imbalance in pretransplant HCTCI scores. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw, renal impairment or other serious adverse events. We conclude that intermittent ZA is effective in preserving long term bone health in HCT recipients at risk for osteoporosis. Disclosures: Hari: Novartis: Research Funding. Vesole:Novartis: Research Funding. Burns:Novartis: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document