Results of a Phase I/II Study of Gemtuzumab Ozogamicin Added to Fludarabine (F), Melphalan (M) and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Relapsed Myeloid Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 841-841 ◽  
Author(s):  
Marcos de Lima ◽  
S. Giralt ◽  
Z. Caldera ◽  
G. McCormick ◽  
M. Qazilbash ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Failure ◽  
Stem Cell ◽  
Blast Crisis ◽  
Conditioning Regimen ◽  
Control Group ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Myeloid Leukemias ◽  
Active Disease

Abstract Most patients (pts) transplanted with active myeloid leukemias will relapse after HSCT. Intensity of the conditioning regimen is an important component of disease control. We hypothesized that GO could safely increase the anti-disease activity of FM, and investigated this hypothesis in the trial reported here. Patients and Methods: Objective: to determine the dose of GO with the lowest toxicity (tox), and the highest response probabilities. Tox: grade 3–4 organ tox, engraftment failure or early death (ED; first 30 days post HSCT). Response was defined as no tox, engraftment, and remission (CR) on day +30. Trial was designed with GO doses of 4, 6 and 9 mg/m2 but given tox observed at 4mg/m2, doses 6 and 9 mg/m2 were not used and dose 2mg/m2 was added. Eligible were pts aged 12–75 years, not candidates for high-dose regimens or with high-risk CD33+ disease. Treatment: GO 2 or 4mg/m2 day -12, F 30mg/m2 (days -5 to -2), M 140mg/m2 (day -2); HSCT day zero. ATG was added in unrelated (UD) HSCT. Graft-versus-host disease (GVHD) prophylaxis: tacrolimus and mini-methotrexate (5mg/m2 day+1,+3,+6,+11). GO was given on day -12 to minimize probability of delaying engraftment. We treated 52 pts, median age 53 yrs (13–72), with AML (n=47), MDS (n=4) or blast crisis CML(n=1). Disease status at HSCT: CR (n=3),induction failure (n=15), first/second relapse (n=33), untreated MDS (n=1). 18 pts had a previous HSCT (allogeneic, n=11 or autologous, n=7). At study entry, median number of bone marrow blasts was 17% (0–95%); 33% of the pts had circulating blasts, 4 pts were FLT3 positive and 38% had poor prognosis cytogenetics. Median blast CD33 expression: 89% (22.5–99.6). Donors: related (n=33) or UD (n=19). Stem cell source was peripheral blood (n=43) or bone marrow (n=9). Results: Median day 30 donor cell chimerism was 100%. Median time to ANC> 500/mm3 was 13 days. Eight pts received GO at 4 mg/m2; 2 died early (due to pneumonia and renal failure) and 2 developed gd III gastro-intestinal and renal tox. 44 pts were then treated at 2 mg/m2: 3 pts died of regimen-related tox (2 ED due to pulmonary bleeding and sepsis, and 1 death within the first 100 days due to pneumonia, renal failure/TTP/HUS). 100-day treatment-related mortality (including 2 deaths due to aGVHD and 1 due to infection) was 15% (n=8). Tox included reversible gd III-IV bilirubin (n=2), transaminase elevation (n=5), moderate hepatic VOD (n=1) and gd I-II GI tract (n=39). CR rate was 90%; 1 pt failed to respond. Gd II-IV and III-IV aGVHD rates were 44% and 23%, respectively, and 58% developed cGVHD. Median follow-up is 9 months (2.5–36) for surviving pts (n=29); 17 pts have relapsed. Median event-free-survival (EFS) is 3.8 mos. Median EFS of a historic control group treated with FM140 (n=36) was 2.2 mos (Figure). Tox of GOFM is similar to that documented by our group with FM140 mg/m2 in a somewhat better prognosis population.(de Lima et al. Blood.2004; 104:865–72) Conclusion: GO 2mg/m2 can be safely added to FM, and may improve the anti-leukemic efficacy of the regimen. EFS - patients with active disease at HSCT EFS - patients with active disease at HSCT

166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2684-2691 ◽  
Author(s):  
Sergio Giralt ◽  
William Bensinger ◽  
Mark Goodman ◽  
Donald Podoloff ◽  
Janet Eary ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
High Dose ◽  
Two Phase ◽  
Hematopoietic Stem

Abstract Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation. (Blood. 2003;102:2684-2691)

scholarly journals Perspectives on the co-treatment with GnRHa in female patients undergoing hematopoietic stem cell transplantation

2017 ◽  
Vol 6 (8) ◽  
pp. R162-R170 ◽  
Author(s):  
Luminita Nicoleta Cima ◽  
Anca Colita ◽  
Simona Fica
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Randomized Clinical Trials ◽  
Conditioning Regimen ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Gonadal Dysfunction

Outcomes after hematopoietic stem cell transplantation (HSCT) for patients with both malignant and nonmalignant diseases have improved significantly in recent years. However, the endocrine system is highly susceptible to damage by the high-dose chemotherapy and/or irradiation used in the conditioning regimen before HSCT. Ovarian failure and subsequent infertility are frequent complications that long-term HSCT survivors and their partners face with a negative impact on their QoL. Several meta-analyses of randomized clinical trials showed that gonadotropin-releasing hormone agonist (GnRHa) administration in advance of starting standard chemotherapy decreases the risk of gonadal dysfunction and infertility in cancer patients, but GnRHa use for ovarian protection in HSCT patients is not fully determined. In this review, we are discussing the potential preservation of ovarian function and fertility in pubertal girls/premenopausal women who undergo HSCT using GnRHa in parallel with conditioning chemotherapy, focusing on the current data available and making some special remarks regarding the use of GnRHa.

scholarly journals Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 60-65 ◽  
Author(s):  
JT Holden ◽  
RB Geller ◽  
DC Farhi ◽  
HK Holland ◽  
LL Stempora ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Acute Leukemias ◽  
Hematopoietic Stem

Thy-1 (CDw90) is a phosphatidylinositol-anchored cell surface molecule which, when coexpressed with CD34 in normal human bone marrow, identifies a population of immature cells that includes putative hematopoietic stem cells. To date, the characterization of Thy-1 expression has been confined largely to normal tissues and cell lines. In this study, we evaluated the frequency and intensity of Thy-1 expression as defined by reactivity with the anti-Thy-1 antibody 5E10 in 38 cases of CD34+ acute leukemia (21 acute myelogenous leukemia [AML], 8 chronic myelogenous leukemia [CML] in blast crisis, and 9 acute lymphoblastic leukemia [ALL]). In 34 of 38 cases (89%) the CD34+ cells lacked expression of the Thy-1 antigen. High-density Thy-1 expression was found in 1 case of CML in lymphoid blast crisis, and low- density Thy-1 expression was identified on a portion of the leukemic cells in 2 cases of AML with myelodysplastic features, and 1 case of CML in myeloid blast crisis, suggesting a possible correlation between Thy-1 expression and certain instances of stem cell disorders such as CML and AML with dysplastic features. In contrast, the dissociation of Thy-1 and CD34 expression in the majority of acute leukemias studied suggests that the development of these leukemias occurs at a later stage than the hematopoietic stem cell. Characterization of Thy-1 expression in acute leukemia may eventually provide insights into the origin of the disease. In addition, separation of leukemic blasts from normal stem cells based on Thy-1 expression may prove useful in assessing residual disease, as well as in excluding leukemic blasts from stem cell preparations destined for autologous bone marrow or peripheral stem cell transplantation.

Comparison of conditioning regimen toxicities among autologous stem cell transplantation eligible multiple myeloma patients: High-dose melphalan versus high-dose melphalan and bortezomib

2017 ◽  
Vol 24 (4) ◽  
pp. 281-289 ◽  
Author(s):  
Eda Aypar ◽  
Fikret Vehbi İzzettin ◽  
Şahika Zeynep Akı ◽  
Mesut Sancar ◽  
Zeynep Arzu Yeğin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Standard Of Care ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Duration Of Hospitalization ◽  
High Dose Melphalan

Background Autologous hematopoietic stem cell transplantation (AHSCT) remains the standard of care for younger patients with multiple myeloma (MM). Currently, high-dose melphalan (HDM) is recommended as conditioning regimen before AHSCT. Preclinical data suggest that combining bortezomib and melphalan has synergistic effect against multiple myeloma cells. Bortezomib and HDM (Bor-HDM) combination as conditioning regimen has been investigated by many other investigators. Objective In this retrospective study, we aimed to compare transplant-related toxicities and hematologic recovery of HDM and Bor-HDM conditioning regimens. Method We retrospectively evaluated hematologic recovery and toxicity profile in patients with MM who received AHSCT with either HDM ( n = 114) or Bor-HDM ( n = 53) conditioning regimen. Results Nonhematologic toxicities were comparable between HDM and Bor-HDM conditioning regimen, except mucositis and diarrhea being more frequent in the Bor-HDM group. Neutrophil and platelet engraftment time and duration of hospital stay were significantly shorter for HDM regimen. Conclusions In this retrospective analysis, we observed engraftment kinetics and duration of hospitalization were significantly worse in Bor-HDM conditioning regimen with manageable toxicities. Randomized studies are needed to further compare Bor- HDM regimen to HDM in terms of response rates, toxicities, and transplant-related mortality.

A Experimental Study and Clinical Result of Prophylaxis aGVHD with Humanized Anti-CD25 Monoclonal Antibody in Haploidentical BMT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1251-1251
Author(s):  
Shu-Quan Ji ◽  
Hui-Ren Chen ◽  
Heng-Xiang Wang ◽  
Hong-Min Yan ◽  
Mei Xue ◽  
...  
Keyword(s):  
Median Time ◽  
Conditioning Regimen ◽  
Control Group ◽  
High Dose ◽  
Marrow Graft ◽  
Hla Antigen ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference

Abstract Between February 1999 and March 2004, eighty-seven patients with high risk leukemia, age 3–50 (median 19 year), who needed urgent transplant but no HLA-matched or single HLA-antigen mismatched donors available, received unmanipulated HLA haploidentical BMT. The 87 patients were classified as follows AML 27 (CR1 in 7, CR2 in 15 and 5 in relapse), All 38 (CR1 in 4, CR2 in 30 and 4 in relapse) , CML 22 ( 4 in CP, 12 in AP and 6 in BP). All donors were HLA-haploidentical relatives who had at least two major histocompatibility complex antigen mismatched with the recipients. 87 patients underwent haplo-BMT with G-CSF primed BM as stem cells. All patients received a same conditioning regimen including high dose Ara-C, Cyclophosphamide, antithymocyte globulin and total body irradiation to provide both immunosuppression and myeloablation. GVHD prophylaxis consisted of anti-thymocyte globulin, cyclosporin A, methotrexate and mycofenolate mofitel. 72 patients underwent the transplants with the addition of CD25 mAb (Basiliximab Novartis) for GVHD prophylaxis designated as CD25 mAb group. Basiliximab 20mg each by 30min intravenous infusion on 2 hours before transplantion and day 4 after transplantaion. The other 15 patients without Basiliximab for GVHD prophylaxis were as the control group. The two group of patients were comparable in disease status, HLA-disparity and median age of patients. Immunophenotyping, limited dilution assay and colony forming assays were used to measure the effect of Basiliximab on the subsets of lymphocytes, cytotoxic T lymphocyte precursors (CTLp) and hematopoietic cells. All donors were primed with G-CSF at 3-5ug/kg/d for 7 days and the marrow cells were harvested on the eighth day. G-CSF donor priming significantly increased CD34+ and colony forming progenitors in the marrow grafts. More importantly, it significantly reduced lymphocytes and reversed CD4+/CD8+ lymphocyte ratio in the grafts. Both of group who were treated with and without Basiliximab had similar marrow graft contents. All patients established trilineage engraftments.The median time to achieve an absolute neutrophil count 0.5x109/L was 19 days (range, 13 to 24 days). The median time to achieve platelets above 20x109/L was 22 days (range, 16 to 32 days). Between the two groups were no differences in engraftment. Incidence of grades II–IV acute GVHD were 13.9% with GVHD-related deaths 6.9% in Basiliximab group and 33.3% with 20% GVHD-related deaths in control group. There were a significant difference between the anti-CD25 mAb treated Vs non-treated group.Forty-nine patients who survived over 12 months were eligible for the evaluation of cGVHD. 12 patients developed extensive cGVHD, one in control group and eleven in Basiliximab group. 49 were alive in CR during a median follow-up of 30 months (range3–64 months), 42 in Basiliximab group and 7 in control group. Basiliximab significantly decreased alloreactive CTLp by 10–100 fold in limiting dilution assays. It had no effect on hematopoietic stem and progenitor cells as determined by in vitro colony-forming assays.The addition of basiliximab as aGVHD prophylaxis effectively reduced severe lethal aGVHD in haplo-BMT. It is possible to selectively eliminate or reduce the number of alloreactive T cells with anti CD25 antibody, which results in prevention of or a reduction in the severity of GVHD.

Antibody-Based Depletion of Hematopoietic Stem Cells Empties Niches for Efficient Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. LB2-LB2
Author(s):  
Agnieszka Czechowicz ◽  
Daniel L. Kraft ◽  
Deepta Bhattacharya ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Conditioning Regimen ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Exact Function ◽  
Potential Applications ◽  
Conditioning Regimens

Abstract Hematopoietic stem cells (HSCs) are used therapeutically in bone marrow/hematopoietic stem cell transplantation (BMT/HSCT) to correct hematolymphoid abnormalities. Upon intravenous transplantation, HSCs can home to specialized bone marrow niches, self-renew and differentiate and thus generate a new, complete hematolymphoid system. Unfortunately BMT has had limited applications, due to the risks associated with the toxic conditioning regimens, such as irradiation and chemotherapy, that are deemed necessary for HSC engraftment. Elimination of these toxic conditioning regimens could expand the potential applications of BMT to include many non-malignant hematologic disorders, a wide variety of autoimmune disorders such as diabetes and multiple sclerosis, as well as in the facilitation of organ transplantation. The exact function of these traditional myeloablative conditioning regimens is not clear. To elucidate the barriers of HSC engraftment, we transplanted 50–1000 purified HSCs (Ckit+Lin−Sca1+CD34+CD150−) into immunodeficient, Rag2−/− or Rag2−/−gc−/− recipient mice and show that HSC engraftment levels rarely exceed 0.5% following transplantation without toxic conditioning, indicating that the immune system is not the only barrier to engraftment. Additionally, we did not observe a significant increase in HSC engraftment when HSC doses of >250 cells were transplanted. Even when up to 18000 HSC were transplanted, we did not see a linear increase in HSC engraftment, indicating that the increased doses of HSCs transplant inefficiently. We believe this is due to the naturally low frequency of available HSC niches, which we postulate may result from the physiologic migration of HSCs into circulation. Conversely, separation of the graft into small fractions and the subsequent time-delayed transplantation of these doses did result in increased engraftment due to the natural physiologic creation of new available HSC niches. When 1800 HSC were transplanted daily for seven days, the engraftment was 6.1-fold higher than transplantation of 12800 HSC in a single bolus. Here, we provide evidence that, aside from immune barriers, donor HSC engraftment is restricted by occupancy of appropriate niches by host HSCs. Through elimination of host HSCs we are able to increase available HSC niches for engraftment. We have developed a novel system where HSCs can be eliminated by targeting C-kit, a cell surface antigen that is highly expressed on the surface of HSCs. Cultivation of HSCs with ACK2, a depleting antibody specific for c-kit, prevented stem-cell factor (SCF) dependent HSC proliferation in vitro and resulted in cell death. Administration of ACK2 to mice led to the rapid and transient removal of >98% of endogenous HSCs in vivo thus resulting in equal numbers of available niches for engraftment. Following ACK2 clearance from serum, transplantation of these animals with donor HSCs led to chimerism levels of up to 90%, representing a 180-fold increase as compared to unconditioned animals. This non-myeloablative conditioning regimen had few side effects, other than temporary loss of coat color. The HSCs in even untransplanted animals rapidly recovered and animals remained healthy and fertile. This work redefines the way we approach BMT/HSCT, and places great emphasis on the necessity to create available HSC niches prior to transplantation. Extrapolation of these methods to humans may enable efficient yet mild conditioning regimens for transplantation, thus expanding the potential applications of BMT/HSCT.

High Dose Valacyclovir Is Highly Effective to Prevent Cytomegalovirus and Other Herpes Viruses Viremia After Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1140-1140
Author(s):  
Marie Detrait ◽  
Guy Boivin ◽  
Robert Delage ◽  
Claire Béliveau ◽  
Annie-Claude Labbé ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Control Group ◽  
High Dose ◽  
Herpes Viruses ◽  
Allogeneic Transplant ◽  
Highly Effective ◽  
Cmv Reactivation

Abstract Abstract 1140 Poster Board I-162 Introduction Cytomegalovirus (CMV) remains the most significant viral pathogen following allogeneic hematopoietic stem cell transplantation. Pre-emptive therapy has now become the most commonly used strategy to prevent CMV disease. However, the use of a very effective anti-viral agent could theoretically minimize the risk of disease caused by CMV and other herpesviridae as well as abrogate prospective surveillance after allogeneic transplant. Valacyclovir, the L-valyl ester oral pro-drug of acyclovir, has excellent bioavailability, resulting in high plasma exposures similar to those following IV acyclovir administration. This property confers to valacyclovir antiviral activity against CMV and other herpesviridae. We hypothesized that universal prophylaxis with valacyclovir until day +100 after allogeneic transplant in recipients at high risk of CMV reactivation would lead to a decreased incidence of CMV viremia. Patients and methods Between 2003 and 2005, we conducted a prospective, randomized study in two allogeneic transplant centers in the Province of Quebec, Canada. Eligibility criteria included therapy with allogeneic blood or marrow transplantation, recipient CMV seropositivity, ability to follow protocol and give informed consent. One group was randomized to receive high dose acyclovir (500 mg/m2 iv TID from day -1 till oral intake was resumed followed by valacyclovir 2000 mg QID until day +100 after transplant (n=32), while the control group was followed using a PCR-based (Cobas system, Amplicor Monitor CMV test, Roche) preemptive approach (n=23). Valacyclovir doses were adjusted according to renal function. In addition, weekly specimens, from before initiation of conditioning regimen until day +100, were also collected in both groups of patients in order to compare incidences of other herpes viruses viremia (HSV, EBV) by real-time PCR. All patients with a positive CMV viremia were immediately treated with ganciclovir 5 mg/kg BID until disappearance of positive signal (minimum of 2 weeks) followed by 2 additional weeks. Recurrences were treated as inititial episodes. Primary end point was incidence of CMV viremia by day +100. Results Both groups of patients were similar regarding age, type of transplant (sibling vs unrelated donor), HLA compatibility, conditioning regimen (myeloablative vs reduced intensity), GVHD prophylaxis, graft nature and content and acute or chronic GVHD incidence. Valacyclovir was highly effective to reduce the incidence of CMV viremia. In the Valacyclovir group, CMV viremia occurred in 6 patients (6/31;19%) compared to 12 (12/23;63%) in the control group. Cox regression demonstrates a protective effect with valacyclovir (HR, 0.28; 95% CI: 0.10-0.74; p=0.01). Time to CMV viremia was identical in both groups (day +39 vs +36); however, the median viral load was lower in the valacyclovir group (748 vs 8043) although this difference did not reach statistical difference. Similar to CMV, both incidences of EBV and HSV viremia were significantly lower in the valacyclovir group (EBV: 4% vs 28%, p=0.005; HSV: 4% vs 30%, p=0.002). Day +100 mortality and at last follow-up are similar in both groups. Valacyclovir use was safe and well tolerated by most allogeneic transplant recipients but required frequent dose modification according to creatinine level. Conclusions Valacyclovir prophylaxis until day +100 is effective to prevent CMV, HSV and EBV reactivation after allogeneic hematopoietic transplantation. Further studies in larger numbers of patients are needed to precise the optimal use of valacyclovir in this patient population. Disclosures Off Label Use: Valacyclovir was used to prevent CMV reactivation following allogeneic transplantation under an experimental protocol approved by our IRB.

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