scholarly journals Targeted IV busulfan and fludarabine followed by post-allogeneic hematopoietic cell transplantation rituximab demonstrate encouraging activity in CD20+ lymphoid malignancies without increased risk of infectious complications

2011 ◽  
Vol 93 (2) ◽  
pp. 206-212 ◽  
Author(s):  
Joseph Pidala ◽  
Jaime Roman-Diaz ◽  
Jongphil Kim ◽  
Taiga Nishihori ◽  
Janelle Perkins ◽  
...  



2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Nicoletta Iacovidou ◽  
Maria Kollia ◽  
Emmeleia Nana ◽  
Theodora Boutsikou ◽  
Christos Savvidis ◽  
...  

Patients with thalassemia major who received allogeneic hematopoietic cell transplantation are at increased risk of gonadal insufficiency and reduced fertility due to the toxicity of both the transfusional iron overload and the gonadotoxic effects of drugs used in the conditioning regimen. We present a case of an ex-thalassemic patient with spontaneous recovery of spermatogenesis that fathered a healthy, term male neonate. Maternal hemoglobin electrophoresis was within normal limits. At the age of 9.5 years the patient underwent hematopoietic cell transplantation. The conditioning therapy included busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). No irradiation was administered. Thirty-two days after the hematopoietic cell transplantation the patient developed acute graft-versus-host disease needing long-term treatment with methylprednisolone, cyclosporine and immunoglobulin. Although consecutive semen analyses after the hematopoietic cell transplantation revealed azoospermia, the last semen analysis before conception, at the age of 33 years, was improved and normal follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (Te) levels were detected. The current pregnancy was the result of physical conception. In this case, it seems that thalassemia major along with the respective treatment prior to- and posthematopoietic cell transplantation did not irreparably impair spermatogenesis, probably due to the pre-pubertal time frame they were implemented. 对于接受异基因造血细胞移植的重型地中海贫血患者,由于输注性铁过载的毒性和预处理方案中所用药物性腺毒性作用这两方面的原因,都使其面临更大的性腺功能不全风险和更低的生育力。本文报道一例精子发生出现自然恢复的原重型地中海贫血患者,他成功孕育出一个健康的足月男婴。母体血红蛋白电泳在正常范围内。患者在9岁半时接受了造血细胞移植。预处理治疗包括白消安(16 mg/kg)和环磷酰胺(200 mg/kg)。未给予照射。造血细胞移植32天后,患者出现急性移植物抗宿主病,需要长期使用甲基强的松龙、环孢素和免疫球蛋白治疗。虽然造血细胞移植后连续的精液分析显示无精子症,但在33岁时受精前的最后一次精液分析有所改善,经检测发现卵泡刺激素(FSH)、黄体生成素(LH)和睾酮(Te)水平正常。目前的怀孕是自然受孕的结果。在这个病例中,看来重型地中海贫血以及造血细胞移植前后相应的治疗并没有对精子发生造成不可恢复的破坏,这可能是由于移植时处于青春发育期前时间段的原因。



Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2460-2460 ◽  
Author(s):  
Radha Ramanan ◽  
Andrew Boon Ming Lim ◽  
Kate Mason ◽  
Jeffrey Szer ◽  
David Ritchie

Abstract Aim To identify the causes and consequences of omission and/or reduction of methotrexate (MTX) doses in graft-versus-host disease (GVHD) prophylaxis used during allogeneic hematopoietic cell transplantation (alloHCT). Method We conducted a retrospective medical record review of 125 alloHCTs performed between the years 2011 and 2013 at our hospital where MTX (15, 10, 10, 10 mg/m2 intravenously on day [D] +1, D+3, D+6, D+11 respectively) is used with cyclosporine as GVHD prophylaxis. The association of MTX dose omission with overall survival (OS), non-relapse mortality (NRM) and acute GVHD, measured from a landmark of D+12, was evaluated with univariate and multivariate analysis. Results 116 patients (median age 48, range 17-67, 59% male) were eligible for analysis. Commonest indications for alloHCT were acute leukemia (47%) and chronic lymphoproliferative disorders (28%). Conditioning was myeloablative in 54%, donors were siblings in 53%, and grafts were peripheral blood in 87%. 85 patients (73%) received all four full doses of MTX. 22 patients had a dose omission at D+11, and two at both D+6 and D+11. 43 patients were given folinic acid rescue. Documented reasons for MTX alteration were mucositis (n = 22; World Health Organisation mucositis grade 4 in 16 patients, grade 3 in 4 patients and grade 2 in 2 patients), fluid overload (n = 10), liver impairment (n = 8, median bilirubin 83 micromol/L, range 19-204 micromol/L, normal < 21 micromol/L), renal impairment (n = 8, median creatinine 138 micromol/L, range 67-276 micromol/L, normal 45-90 micromol/L) and sepsis (1). MTX omission was associated with poorer OS (48% vs 90%; hazard ratio [HR] for mortality 5.4, 95% CI 2.5-11.7, P < 0.001, Figure 1) and higher NRM (39% vs 5%, HR 10.2, 95% CI 3.4-30.8, P < 0.001, Figure 2) at 12 months post landmark. A pattern of ongoing NRM was observed beyond day 100. Strikingly, those patients who received all four full doses of MTX had NRM of 0% at 100 days post landmark. There was no difference in rates of grade 2-4 (24% vs 22%, P = .950) or grade 3-4 (9% vs 11%, P = .662) acute GVHD, or relapse (20% vs 17%, P = .514), at day 100 post landmark. Conclusion MTX dose reduction has no significant impact on GVHD development, suggesting that MTX omissions or other adjustments of GVHD prophylaxis did not lead to enhanced T cell activation. However, it seems that the need to reduce MTX indicates an increased risk of NRM, likely reflecting ongoing organ dysfunction. Older patients or those with pre-transplant co-morbidities may be better served by strategies that lower the likelihood of organ toxicity, including reduced intensity conditioning and lower initial doses of MTX. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 1. Overall survival according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Figure 2. Non-relapse mortality according to whether or not any methotrexate (MTX) was omitted. Disclosures No relevant conflicts of interest to declare.



Author(s):  
Madhavi Lakkaraja ◽  
Michael Scordo ◽  
Audrey Mauguen ◽  
Christina Cho ◽  
Sean M. Devlin ◽  
...  

Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+IR) leading to higher mortality. In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+ ≥50/µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to define an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used. 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0-101). Low post-HCT AUC (&lt;30AU*d/L) was associated with lower risk of NRM (p&lt;0.01) and higher probability of achieving CD4+IR (p&lt;0.001). Patients who attained CD4+IR had a 7-fold lower 5-year NRM (p&lt;0.0001). Probability of achieving CD4+IR was 2.5-fold and 3-fold higher in the &lt;30AU*d/L-group, compared to 30-55AU*d/L and ≥55AU*d/L-groups, respectively. In multivariable analyses, post-HCT rATG-exposure ≥55AU*d/L was associated with an increased risk of NRM (HR 3.42,95%CI 1.26-9.30). In the malignancy subgroup (n=515) a 10-fold and 7-fold increased NRM, was observed in the &gt;55AU*d/L and 30-55AU*d/L groups, respectively, compared to &lt;30AU*d/L group. Post-HCT rATG exposure ≥55AU*d/L was associated with higher risk of acute GVHD (HR 2.28,95%CI 1.01-5.16). High post-HCT rATG-exposure is associated with higher NRM secondary to poor CD4+IR after TCD-HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.



Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 664-664 ◽  
Author(s):  
Robert W. Chen ◽  
Stephen J. Forman ◽  
Joycelynne Palmer ◽  
Ni-Chun Tsai ◽  
Leslie Popplewell ◽  
...  

Abstract Abstract 664 Background: The prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous hematopoietic cell transplantation is poor. Although reduced intensity allogeneic hematopoietic cell transplantation (RIC allo-HCT) can induce durable remissions in some patients with relapsed/refractory HL, its use is limited by a lack of disease control prior to transplantation. Brentuximab vedotin (b-vedotin, SGN-35), a novel antibody-drug conjugate, has a 75% objective response rate in patients with relapsed/refractory HL (Chen 2011). To examine the impact of b-vedotin on RIC allo-HCT, we performed a retrospective analysis of relapsed/refractory HL patients who received b-vedotin at City of Hope National Medical Center (COH) and Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA) and then went on to receive RIC allo-HCT. Methods: Between October 2008 and July 2011, 46 patients with relapsed/refractory HL received b-vedotin at COH and SCCA through Seattle Genetics trials (SGN-35-03, 06, 07, and 08). 16/46 (34.8%) patients subsequently underwent RIC allo-HCT, including 12 at COH (2/12 were transplanted at University of Utah and Wellington Hospital) and 4 at the SCCA. The baseline characteristics are listed in Table 1. All 12 COH patients received fludarabine/melphalan as the conditioning regimen, 5/12 used matched related donors and 7/12 used matched unrelated donors. 10/12 received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis and 2 patients received mycophenolate mofetil (MMF) and cyclosporine (CSP). In contrast, 3/4 patients transplanted at the SCCA received haploidentical donors transplantation using fludarabine/cytoxan/2Gy TBI conditioning and cytoxan/tacrolimus/MMF as GVHD prophylaxis while 1/4 underwent conditioning using 2Gy TBI followed by CSP/MMF prophylaxis. Patients were monitored for engraftment, aGVHD, cGVHD, chimerism, and infectious complications per institutional standards. Each institutional review board approved the retrospective analysis of individual center data and we plan to present combined analysis of COH/SCCA data at ASH. Results: At COH, the 1 year PFS was 90% (95% CI: 54.0, 98.2) and the 1 year OS was 100% with a median follow-up of 13.2 months (range: 2, 20), In addition, the 1 year relapse rate was 10% (95% CI: 1.7, 46) and the non-relapse mortality at 1 year was 0%. Likewise, all 4 of the SCCA patients are alive and progression-free with a median follow up of 7.2 months (range: 2.9, 19). For the entire cohort the rates of aGVHD and cGVHD were 25% and 63%, respectively. There was no grade III-IV aGVHD and only 1/16 (6.3%) with extensive cGVHD. There was no delay of engraftment or increased incidence of CMV/EBV infections (Table 1). The only patient who relapsed after RIC allo-HCT had progressive disease at the time of transplantation, and 276 days had elapsed between the last dose of b-vedotin to RIC allo-HCT. Conclusion: These data suggest that b-vedotin prior to RIC allo-HCT in HL can yield prolonged disease control without a delay in engraftment, increase in non-relapse mortality, aGVHD, cGVHD, and post transplant infectious complications. Such a strategy may allow more patients with relapsed or refractory HL to gain sufficient pre-transplant disease control to undergo this potentially curative procedure. Disclosures: Chen: Seattle Genetics: Consultancy, Research Funding. Off Label Use: SGN-35, a novel antibody drug conjugate, is used as salvage therapy for relapsed hodgkin lymphoma prior to allogeneic hematopoietic cell transplantation. Grove:seattle genetics: Employment. Gopal:Bio Marin: Research Funding; SBio: Research Funding; Pfizer: Research Funding; Abbott: Research Funding; Millenium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Piramal: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Spectrum: Research Funding; GSK: Research Funding; Biogen-Idec: Research Funding.



Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2744-2748 ◽  
Author(s):  
Christoph Kahl ◽  
Barry E. Storer ◽  
Brenda M. Sandmaier ◽  
Marco Mielcarek ◽  
Michael B. Maris ◽  
...  

Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m2; n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.



Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 939-944 ◽  
Author(s):  
Debra L. Friedman ◽  
Alicia Rovo ◽  
Wendy Leisenring ◽  
Anna Locasciulli ◽  
Mary E. D. Flowers ◽  
...  

As risk for secondary breast cancer is elevated among cancer survivors treated with conventional therapy, we sought to determine the risk among 3337 female 5-year survivors who underwent an allogeneic hematopoietic cell transplantation (HCT) at the Fred Hutchinson Cancer Research Center or at one of 82 centers reporting to the European Bone Marrow Transplant Registry. Risk was calculated using standardized incidence ratios (SIRs), and risk factors were evaluated with a multivariable Cox proportional hazards model. Fifty-two survivors developed breast cancer at a median of 12.5 (range: 5.7-24.8) years following HCT (SIR = 2.2). Twenty-five–year cumulative incidence was 11.0%, higher among survivors who received total body irradiation (TBI) (17%) than those who did not receive TBI (3%). In multivariable analysis, increased risk was associated with longer time since transplantation (hazard ratio [HR] for 20+ years after transplantation = 10.8), use of TBI (HR = 4.0), and younger age at transplantation (HR = 9.5 for HCT < 18 years). Hazard for death associated with breast cancer was 2.5 (95% CI: 1.1-5.8). We conclude that female survivors of allogeneic HCT are at increased risk of breast cancer and should be educated about the need for regular screening.



Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2876-2876
Author(s):  
Sebastian Giebel ◽  
Myriam Labopin ◽  
Gerard Socie ◽  
Mahmoud Aljurf ◽  
Urpu Salmenniemi ◽  
...  

Abstract BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard of care for adults with high-risk acute lymphoblastic leukemia (ALL) in first or subsequent complete remission (CR). Myeloablative total body irradiation (TBI) combined with cyclophosphamide (Cy) is the most frequently used conditioning regimen. In order to reduce toxicity Cy may be replaced by fludarabine (Flu). The goal of this registry-based, retrospective study was to compare outcomes of allo-HCT following TBI/Cy vs. TBI/Flu conditioning. PATIENTS AND METHODS: Included in the analysis were 2255 patients aged 18-65 years, treated with allo-HCT from either a matched sibling (43%) or unrelated (57%) donor in CR1 (83%) or CR2 (17%), between the years 2010-2020. Patients with Ph(-) B-ALL, Ph(+) B-ALL, and T-ALL were represented in equal proportions. TBI 12Gy + Cy was used in 2105 cases while TBI 12Gy + Flu was administered to 150 patients. Patients treated with TBI/Flu were significantly older (median 35 years vs. 33 years, p=0.006), with poorer Karnofsky performance score (&lt;90, 27% vs. 20%, p=0.03), more frequently transplanted from unrelated donors (71% vs. 57%, p=0.0007) with less frequently use of bone marrow as a source of stem cells (5% vs. 21%, p&lt;0.0001), and in more recent year (median 2018 vs. 2015, p&lt;0.0001). RESULTS: Engraftment rate was 99% for both TBI/Cy and TBI/Flu patients. In a univariate analysis the use of TBI/Cy as compared to TBI/Flu was associated with a tendency to reduced incidence of relapse (24% vs. 29% at 2 years, p=0.1), increased incidence of grade 2-4 acute graft versus host disease (GVHD, 35.5% vs. 28%, p=0.08) and improved leukemia-free survival (LFS, 62% vs. 57%, p=0.18). The rates and causes of non-relapse mortality (NRM) did not differ significantly between the two conditioning groups. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with reduced risk of relapse (HR=0.69, p=0.049) and increased risk of grade 2-4 acute GVHD (HR=1.57, p=0.03) without significant effect on other transplantation outcomes. An additional analysis was performed with TBI/Cy treated patients (n=132) matched strictly to those treated with TBI/Flu (n=132) in terms of disease subtype, disease status and donor type with the nearest neighbor for patient age, patient and donor sex, in vivo T-cell depletion, Karnofsky score and source of stem cells; the use of TBI/Cy as compared to TBI/Flu was associated with significantly reduced rate of relapse (18% vs. 30% at 2 years, p=0.015) and a tendency to an improved LFS (65% vs. 59%, p=0.07) and overall survival (OS, 73% vs. 68%, p=0.16) without effect on NRM and GVHD. CONCLUSIONS: The use of myeloablative TBI/CY as conditioning prior to allo-HCT for adult patients with ALL in CR1 or CR2 is associated with stronger anti-leukemic effect leading to significantly lower relapse rate compared to TBI/Flu and therefore should be likely considered a preferable regimen. Disclosures Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Labopin: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Forcade: Novartis: Consultancy, Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support. Huynh: Jazz Pharmaceuticals: Honoraria. Spyridonidis: Menarini: Current Employment. Perić: therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Mohty: Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria.



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