Pharmacokinetics and Clinical Activity of Very Low Dose (10mg) Alemtuzumab In Transplantation for Acute Leukemia.

Abstract Abstract 1275 The impressive safety and efficacy demonstrated with the in vivo use of the rat Campath-1G led to the introduction of the commercially available humanized Campath-1H (alemtuzumab) with the same schedule, i.e. total dose (TD) 100mg and later the TD was reduced to 50mg. However, studies with such high doses of alemtuzumab revealed increased incidence of relapse and severe viral infections. The most probable explanation for the untoward effects seen turned out to be the prolonged half-life of alemtuzumab (15-21 days) as compared to rat Campath-1G (13 hours). Pharmacokinetic studies showed that the peak serum alemtuzumab levels with the 100mg and 50mg schedule were 13700 ng/ml and 2500 ng/ml, respectively. Concentrations remained at high levels >1000 ng/ml at least 4 weeks (TD 100mg) and >500 ng/ml at least 2 weeks (TD 50mg), and thus far above the lymphotoxic levels of 100ng/ml. We report here for the first time pharmacokinetic studies and clinical activity of very low dose alemtuzumab (TD 10mg) in transplantation for acute leukemia. 18 consecutive pts (median age 38y, 20–65) with acute leukemias (AML 12, ALL 6 pts) underwent sibling (39%) or unrelated (61%) allogeneic transplantation and received a TD of only 10 Campath-1H (5mg/d at d-2 and d-1) as part of the conditioning and post-transplant cyclosporine (Cya) without methotrexate. 39% of patients had advanced disease (>CR1) at tranpslant. Conditioning was BuCy=7, TBI/VP16/Cy=4, Flu/BCNU/Thiotepa +/− HD-ARA-C=10. All pts except one received peripheral blood stem cells. All pts engrafted promptly (WBC>1.000/μl on d+14, 11–21 and PLT> 20.000/μl on d+12, 7–27). 17% pts developed grade I skin acute GVHD, 11% VUD-recipients developed steroid-sensible grade II acute GvHD and further 2 (11%) VUD-recipients, who had refractory AML at transplant, developed GvHD III after early Cya discontinuation (d+43, d+95). TRM on d+100 was 0. Cya was stopped at median on d+109 (30-202). Chronic GvHD observed in only 2 patients (1 limited, 1 fulminant and fatal liver GvHD on d+143 in a HbsAg +/+ pair). 72% seropositive patients revealed CMV reactivation but no CMV disease occurred. A median absolute CD4 count higher than 200/μL was reached at 9 months. After a median follow up of 200 days (71-486), 14/18 pts are alive and in CR (Karnofsky 100%) and 4 died (relapse n=1, TRM n=3). Causes of death were liver GvHD, H1N1 infection and post-DLI GvHD. We measured serum alemtuzumab levels in 8 patients (5 AML, 3 ALL) with a sensitive (limit of detection 31.25 ng/ml) ELISA technique (performed at BioAnaLab Ltd, Oxford, UK). A total of 54 samples (median 7 samples/patient) were tested from d-2 (15 minutes after the end of the first infusion of 5mg Campath-1H) up to d+30 after transplantation. The median serum peak level was 176 ng/ml (range 135–281) and was found at day of transplantation (day 0). Alemtuzumab levels declined slowly thereafter reaching a median serum level at d+7 of 78 ng/ml (41-114) and at d+20 just above the detection limit (median 42 ng/ml). Alemtuzumab was still detected only in 1 out of 4 patients at day+30. Campath levels were not influenced by disease (AML vs ALL), body weight or body surface area (r2 test). Taken together, with our administration dose and timing (5mg/d at d-2 and d-1) we achieve the maximum peak level at day of stem cell infusion which is lymphotoxic but still 1–2 log lower as compared with the 100mg and the 50mg schedules. Levels decline fast thereafter and at the time of engraftment nearly no Campath antibody remains in the patient's serum. Such fast clearance of the low dose alemtuzumab may prove beneficial regarding safety and GvL efficacy. Though the follow-up period is still relatively short, the clinical results reported here are very encouraging. Disclosures: No relevant conflicts of interest to declare.

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Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone.

Blood ◽

10.1182/blood.v104.11.730.730 ◽

2004 ◽

Vol 104 (11) ◽

pp. 730-730 ◽

Cited By ~ 3

Author(s):

Edwin P. Alyea ◽

Shuli Li ◽

Haesook Kim ◽

Corey Cutler ◽

Vincent Ho ◽

...

Keyword(s):

Serum Level ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Peripheral Blood Stem Cells ◽

Dose Methotrexate ◽

Gvhd Prophylaxis ◽

Low Incidence

Abstract Sirolimus (rapamycin) is a macrocyclic lactone similar in structure to tacrolimus and cyclosporine (CSA) but with a distinct mechanism of action. Sirolimus binds to both FKBP12 and mTOR and inhibits signal transduction and cell cycle progression. The drug is synergistic with tacrolimus but has a distinct toxicity profile, thereby allowing their use in combination. We report results of a phase II trial combining sirolimus with tacrolimus and low-dose methotrexate (MTX) as GVHD prophylaxis in matched related and unrelated donor NST. Results of this trial were compared with patients who had previously undergone NST receiving tacrolimus/MTX alone or CSA/prednisone(pred). All patients received fludarabine (30 mg/m2/d x 4days) and intravenous busulfan (0.8mg/kg/d x 4 days) as conditioning. All patients received G-CSF mobilized peripheral blood stem cells with a targeted cell dose of 1 x 107 CD34+ cells/kg. G-CSF 5 mcg/kg was started on day 1. Sirolimus containing GVHD prophylaxis included sirolimus 12 mg loading dose on day −3 and then 4 mg po qd targeting a serum level of 3–12 ng/ml. Tacrolimus was initiated at 0.05 mg/kg po b. i.d. beginning day −3 with a targeted serum level of 5–10 ng/ml. MTX (5 mg/m2) was given days, 1, 3 and 6. Planned taper of the GVHD medications was ~30% at days 60, and 120 with discontinuation by day 180. The median follow up is 14 months for patients receiving sirolimus and all evaluable patients have been followed for >100 days. 40 patients have been transplanted, 20 from related and 20 from unrelated donors. The median age was 57 years (range 20–69). Diseases included: NHL (9), MDS (7), Hodgkin’s disease (6), CLL (6), AML(5), CML (5), MM (1) and CMML(1). 18 patients (45%) had received prior myeloablative transplantation. 31 patients (78 %) had advanced disease at the time of transplantation. Patients receiving tacrolimus/MTX (n=36) and CSA/pred (n=49)had similar characteristics. Sirolimus was well tolerated and no severe adverse events related to the drug were noted. Acute grade 2–4 GVHD was significantly reduced in patients receiving sirolimus/tacrolimus/MTX, 8% vs 18% in patients receiving tacrolimus/MTX and 37% in those receiving CSA/Pred (p=0.003). Time to neutrophil engraftment was slower in methotrexate containing regimens (13 days vs 9 days, p=0.01), but there was no difference between sirolimus/tacrolimus/MTX and tacrolimus/MTX alone. Median donor derived hematopoiesis, measured 1–2 months after transplant, was high in all groups (sirolimus/tacrolimus/MTX 91%, tacrolimus/MTX 95% and CSA/pred 90%, p=0.91). The 1 year overall survival was sirolimus/tacrolimus/MTX 71%, tacrolimus/MTX 48% and CSA/pred 45% (p=0.17). 1-year progression free survival was 49%, 27% and 37%, respectively (p=0.11). The addition of sirolimus to tacrolimus and low dose MTX is well tolerated and is associated with a low incidence of acute GVHD. The addition of sirolimus does not delay engraftment compared with tacrolimus/MTX and results in a similar high level of donor derived hematopoiesis. Further patient accrual and longer follow-up is needed to yield information on the incidence of chronic GVHD and overall outcome.

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Low-Dose Methotrexate as Salvage Therapy for Refractory Graft-Versus-Host Disease (GVHD) after Reduced-Intensity Conditioning (RIC) for Allogeneic Stem Cell Transplantation (allo-SCT).

Blood ◽

10.1182/blood.v106.11.1802.1802 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1802-1802

Author(s):

Mohamad Mohty ◽

Hugues de Lavallade ◽

Catherine Faucher ◽

Sabine Furst ◽

Jean El-Cheikh ◽

...

Keyword(s):

Side Effects ◽

Salvage Therapy ◽

Low Dose ◽

Acute Gvhd ◽

Chronic Gvhd ◽

High Risk Population ◽

High Morbidity ◽

Dose Methotrexate ◽

Grade 3

Abstract Background. RIC regimens are increasingly used for allo-SCT. Although such regimens are associated with a relatively low early transplant-related mortality (TRM) in comparison to standard myeloablative allo-SCT, GVHD remains a matter of concern. Of note, corticosteroid-resistant GVHD is associated with high morbidity and mortality, and therapeutic options are limited for those patients. Furthermore, patients undergoing RIC allo-SCT are older than patients undergoing myeloablative allo-SCT, and are thus more exposed to the side effects and complications of long term corticosteroids (CS) administration. Low dose methotrexate (MTX) therapy is a well established modality for prophylaxis of GVHD after standard myeloablative allo-SCT. However, little is known about the role of this drug in the treatment of CS-resistant GVHD. Patients and Methods. The aim of this pilot single center study was to investigate the role and benefit of MTX in a curative setting after failure of CS treatment in 20 consecutive patients undergoing RIC allo-SCT. 20 patients experiencing severe GVHD received IV infusions of low dose MTX (5 mg/m2/infusion) at weekly intervals, for at least four weeks. Reasons for MTX administration were: refractory acute GVHD (after at least one week of 2 mg/Kg CS administration), CS-refractory chronic GVHD, chronic GVHD exacerbation after CS taper, or CS side effects and complications (CS-induced diabetes requiring insulin therapy, severe metabolic or psychiatric disorders). Responses to low dose MTX infusions were assessed one month after the last infusion in each involved organ. Results. 12 patients were treated for severe acute GVHD, while 8 patients received MTX for extensive chronic GVHD. Median age of patients was 51 (range, 22–60). Median time of administration of MTX was day +89 (range, 32–300) after allo-SCT. Of note, none of the patients received any other concomitant therapy for refractory GVHD. 13 patients responded to MTX administration (65 %) with 5 complete responses (25%). Among the 12 patients treated for acute GVHD, 7 responded (58%) of whom 5 CRs (42%). 3 patients did not respond and died from resistant GVHD. Interestingly, 5 patients from the group of grade 3–4 acute GVHD responded. Among the 8 patients treated for chronic GVHD, 6 were responders (75%). In addition, MTX allowed a significant reduction of CS daily dosage ranging from 25% to 80%, as assessed one month after the last administration of MTX. With a median follow-up of 287 days, no increase of CS therapy was necessary among these 6 MTX-responding patients. In the whole study population, toxicity of low dose MTX administration was low (transient and mild reversible cytopenia in 3 cases, 15%). Among the 20 patients, 14 are still alive (70%) with a median follow-up of 293 (range, 65–513) days. Overall, 2 patients died of progressive disease, while 4 patients died from refractory GVHD. Conclusions. In this study, the global response rate of severe GVHD to low dose MTX was impressively high (65%) if considered in terms of salvage therapy in this relatively elderly and high risk population. Low dose MTX appears to be a well-tolerated, inexpensive and likely steroid-sparing agent that is worthy of further investigation in prospective trials for treatment of refractory GVHD, but also as frontline therapy in combination with CS.

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Outcome of Busulfan and Fludarabine-Based Reduced Intensity Conditioning Regimen for Related and Unrelated HSCT in Fanconi Anemia Patients

Blood ◽

10.1182/blood.v118.21.1964.1964 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1964-1964

Author(s):

Saba Azarnoush ◽

Raphael Porcher ◽

Regis Peffault de la Tour ◽

Karima Yakouben ◽

Benedicte Bruno ◽

...

Keyword(s):

Bone Marrow ◽

Low Dose ◽

Acute Gvhd ◽

Bone Marrow Failure ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Secondary Malignancy ◽

Secondary Malignancies ◽

Reduced Intensity

Abstract Abstract 1964 Rationale: HSCT is the only curative treatment for Fanconi Anemia (FA) pts with either bone marrow failure or MDS/Leukemia. Due to characteristic chromosomal instability, the poor outcome of FA pts transplanted after so-called conventional myelo-ablative conditioning regimen has been proved. Then, reduced-intensity conditionning regimen (RIC) has been considered for years as a model for allogeneic HSCT in FA pts. The use of fludarabine-based cond' regimen from about 2000 increased dramatically the overall survival of FA pts. Different Flu-based RIC were developed. Patients and method: Between Feb'02 and Dec'10, 17 FA pts from 3 academic French centers were included: 11 from R. Debre hospital, 5 from St Louis hospital and 1 from J. de Flandre hospital. All pts underwent HSCT because of bone marrow failure. They presented no MDS or leukemia. All time-to-event outcomes were counted from the date of HSCT to the date of event or date of last follow-up, except acute GVHD that was arbitrarily censored at 200 days. Death was considered as a competing risk in analyses of neutrophil and platelet recovery and chronic and acute GVHD. Overall survival was estimated using Kaplan-Meier product-limit estimator. For competing risks analyses, cumulative incidences were estimated using usual methodology. Results: Median age at diagnosis and at HSCT were 4.7 years (range 1,8-9,3) and 7,4 years (range 4,4-15,2), respectively. 12 pts presented with less than 3 FA-related malformations and 5 with more than 3 malformations. 2 patients received more than 20 transfusions before HSCT, whereas 8 pts received less than 20 transfusions and 7 patients did not received any. 2 patients received androgen therapy before HSCT. All patients received the same RIC i.e. fludarabine 30mg/m2/d × 3d, cyclophosphamide 10mg/kg/d × 4d and IV busulfan (Bu) 0.75 of body weight- adjusted recommended dose (equivalent to 6.4mg/kg total dose of oral Bu). This RIC did not contain any irradiation. Graft versus-host disease (GvHD) prophylaxis consisted of CSA associated with MMF or corticosteroids. Donors were either matched related (sibling, n= 6; other, n=2) or unrelated (10/10, n= 6; 9/10, n= 3). Stem cell sources were BM (n=10), UCB (n=4) and PBSC (n=2). 9 out of 17 pts had a donor from the same gender whereas 4 male recipients received transplant from female donor. CMV status were −/−, −/+, +/− and +/+ for 8, 4, 1 and 4 D/R pairs, respectively. Median follow-up was 32 months (range 3–102). Successful engraftment was obtained in all patients with a median time for neutrophil recovery of 17 days (range 10–42). All patients presented with 100% donor chimerism. One patient experimented secondary graft failure and died at D291 from infection and renal failure. During transplant procedure, 13 pts experimented at least one severe infectious complication (staphylococcus n=2; pseudomonas n=1; aspergillus n= 2; candida n=2; viral reactivation n= 13). 1 pt presented with moderate hepatic veno-occlusive disease. Five pts died from TRM and 12 pts remained alive in a good health condition. 36 month OS was 69% (95%CI 50 to 96). Cumulative incidence of grade 2 to 4 acute GVHD was 71% (95%CI: 41–87). 5 pts presented with either limited (n=4) or extensive (n=1) chronic GvHD and 36 month cumulative incidence of chronic GVHD was 33% (95%CI 11 to 58). To date, no pt had secondary malignancy. Discussion: Our study confirms the good results obtained by other groups when using flu-based RIC in FA pts. Indeed, satisfying engraftment and long-time survival rates were obtained without any TBI, irrespective of the stem cell source and the donor type. However, we have a concern regarding the cGVHD rate we obtained. As demonstrated by an on-going study of EBMT registry, the risk of secondary malignancy in these pts is statistically correlated to cGvHD. Then, this rate still remains probably too high in our study, even though only one pt presented with extensive cGvHD and no pts developed any secondary malignancy. But this could be explained by the short follow-up. Suppression of one alkalyting agent may reduce both cGVHD incidence and other tissue injuries leading to secondary malignancies. Then, we claim for suppression of Bu for related donor HSCT. In FA pts receiving transplant from unrelated donor, the relative impact of either low-dose IV-Bu – as we used here - or low-dose irradiation on toxicity and especially development of secondary malignancies remains to be evaluated. Disclosures: No relevant conflicts of interest to declare.

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Adult Matched Sibling Blood Cell Transplants (BCT) after Myeloablative Conditioning Incorporating Daily Intravenous (IV) Busulfan (BU) and Low-Dose Antithymocyte Globulin (ATG): Outcomes with Particular Respect to Transplant-Related Mortality (TRM) in 140 Patients.

Blood ◽

10.1182/blood.v104.11.2313.2313 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2313-2313

Author(s):

James A. Russell ◽

Ahsan M. Chaudhy ◽

Oluyeme Jeje ◽

Diana Quinlan ◽

Douglas Stewart ◽

...

Keyword(s):

Acute Leukemia ◽

Low Dose ◽

Acute Gvhd ◽

Myocardial Infarct ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Increase Risk ◽

Cell Transplants ◽

One Year ◽

Related Mortality

Abstract Intravenous BU allows more predictable exposure and is more convenient to administer once daily than the conventional four times daily regimen. Low-dose pretransplant ATG may reduce morbidity and mortality from graft-versus-host disease (GVHD). We have investigated a myeloablative regimen incorporating these agents in 140 adults aged 18–65 (median 47) receiving a first MRD SCT between 05/99 and 01/04. Conditioning comprised fludarabine (FLU) 50mg/m2on days −6 to −2 and IV BU (Busulfex, ESP Pharma) 3.2 mg/kg daily days −5 to −2 inclusive (FLUBUP) in 116 patients (pts) with additional TBI 200cGy x 2 in 24 (14 ALL, 8AML, 2 biphenotypic). Forty-three pts had standard-risk (SR) acute leukemia in CR1 (35 AML, 8 ALL), and 23 had active acute leukemia (HA) (18 AML±MDS, 3 ALL, 2 biphenotypic). A third group of 74 other (OTH) pts comprised 2 AML CR2, 2 ALL CR2, 2 CML (1 AP, 1CP2), 13 MDS, 11 MM, 24 NHL, 6 HD (2 with CLL), 8 CLL, 5 other. All pts were given cyclosporine A, “short course” methotrexate with folinic acid and Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Followup of survivors is 6–61 months, median 26. Incidence of acute GVHD (aGVHD) grade II–IV was 19±4%, grade III–IV 6±2% and chronic GVHD (cGVHD) 66±5% (at 2 years). Projected TRM is 4±2% at 100 days, 10±3% at 1 year and 14±4% at 5 years. For acute leukemia pts projected TRM at one year is 5±5% vs 12±5% with (n = 24) and without (n = 47) TBI respectively (p = ns). Four non-relapse deaths occurred before day 100 one each from myocardial infarct (MI), acute GVHD, candidiasis and VOD. Ten deaths between days 102–569 were related to aGVHD in one and complications in pts with cGVHD in 9 (occurring in 1 pt after 2nd BCT for graft failure) including 1 VZV, 3 other infection, 1 PE, 1 MI. Of 11 follicular NHL pts 3 died of cGVHD and its complications after 1st BCT compared with 5 of 129 others (p = 0.02). Twelve of the transplant-related deaths were in 76 pts ≥ 46 years old compared with 2 in 64 younger pts (TRM = 23±6%, vs 4±3%, p = 0.01). Of 55 relapsed pts 17 are alive, 8 of these are in remission after more treatment and/or onset of GVHD. Projected 5-year disease-free survival and survival respectively is 46±5% and 57±5% for all pts, 62±8% and 76±7% for SR, 51±7% and 59±9% for OTH, and 9±6% and 16±8% for HA. This study indicates that: 1) regimen related mortality is low in MRD BCT recipients given this regimen 2) cGVHD is the main cause of TRM 3) pts with follicular NHL seem to be comparatively susceptible to death related to cGVHD 4) addition of 400cGy TBI does not increase risk of TRM and 5) older age remains a risk factor for TRM.

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Hematopoietic Stem Cell Transplantation (SCT) for Hematologic Malignancy from Matched Related Donors (MRD) with a Myeloablative Once Daily IV Busulfan (Bu)/Fludarabine (Flu) Based Regimen (FLUBUP) with Thymoglobulin: Outcomes in 200 Patients with over One Year Follow-Up.

Blood ◽

10.1182/blood.v108.11.3009.3009 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3009-3009

Author(s):

James A. Russell ◽

Nizar J. Bahlis ◽

Mary Lynn Savoie ◽

M. Ahsan Chaudhry ◽

A. Robert Turner ◽

...

Keyword(s):

High Risk ◽

Acute Leukemia ◽

Graft Failure ◽

Acute Gvhd ◽

Hematologic Malignancy ◽

Chronic Gvhd ◽

Disease Stage ◽

Once Daily ◽

One Year

Abstract Earlier reports indicated that a myelablative protocol based on once daily IV Bu with Flu plus rabbit antithymocyte globulin appeared effective and relatively well tolerated. Since 1999 this has been our standard regimen for all pts with hematologic malignancy, including those who might otherwise be candidates for non-myeloablative regimens. Two hundred MRD SCT patients (pts) were treated between 05/99 and 07/05. Chemotherapy comprised fludarabine 50mg/m2 on days -6 to -2 and IV busulfan (Busulfex, PDL Pharma) 3.2 mg/kg daily days -5 to -2 inclusive. Forty-six acute leukemia pts had additional TBI 200cGy x 2 on day (D) -1 or 0. Prophylaxis for GVHD was cyclosporine A, methotrexate with folinic acid and Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. Cell source was mobilized blood cells (BCT) in 172 and marrow (BMT) in 28. Median age was 46 (range 18–65) and follow-up of survivors was 13–87 months (median 42). As engraftment and GVHD did not differ significantly data for BMT and BCT were combined. Two pts had graft failure (1 with autologous recovery) and two died before D28. The remaining 196 evaluable pts engrafted granulocytes at median of 16 days (range 2–42). Platelets engrafted in 194 pts at a median of 18 days (0–101), 2 died before engraftment on days 29 & 72. Incidence of acute GVHD grade II-IV, acute GVHD grade III-IV and chronic GVHD was 14±2%, 3±1% and 54±4% respectively. Five pts died before D100 of GVHD (1), candidiasis (1), influenza B (1), veno-occlusive disease (1) and myocardial infarction (1), after D100 15 deaths were related to GVHD (11), pneumonia/ARDS (2), graft failure (1) and pulmonary embolus (1). One case of PTLD resolved with rituxan, there was no serious neurological toxicity. For low-risk (acute leukemia CR1/CR2, CML CP1) pts 3 year TRM was 4±3% for those ≤45 years old (n = 54) and 6±4% for those >45 (n = 31). Corresponding figures for all others (high risk) were 6±4% (n = 40) and 27±7% (18±5% at one year, n = 75) (p = 0.04). [table 1] We conclude that FLUBUP appears to be well-tolerated with little mortality attributable to the regimen itself. In partular, concerns about excessive immune suppression (partularly causing PTLD) and neurotoxicity have not been substantiated. Chronic GVHD is the major cause of non-relapse death. Control of early morbidity and mortality from GVHD may allow intensification of the regimen, for example by adding TBI. There is also evidence that the safety can be improved by monitoring Bu levels. The effect of age on TRM is only apparent in high-risk pts, the challenge is to reduce mortality from chronic GVHD in these individuals without sacrificing graft-vs.-malignancy. 3 year outcomes (%) for groups with >10 pts Disease/stage n survival TRM * p = 0.07 AML CR1/2 (no TBI) 32 66±8 9±5 AML CR1/2 (TBI)* 16 94±6 0 AML advanced (no TBI) 18 22±10 17±9 MDS 15 79±11 24±12 ALL CR1/2 15 73±11 8±7 CML CP1 22 100% 0 CLL/Richter’s (as primary indication) 14 68±13 16±10 Multiple Myeloma 13 54±14 8±7 NHL (low grade/mantle) 21 75±10 17±9 All pts 200 66±3 12±3

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Azacitidine Administration Following Hematopoietic Stem Cell Transplantation Is Safe and Feasible in Children with Acute Leukemia

Blood ◽

10.1182/blood.v128.22.4805.4805 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4805-4805 ◽

Cited By ~ 1

Author(s):

Justin T. Wahlstrom ◽

Biljana N. Horn ◽

Carol Fraser-Browne ◽

Rebecca Hoeweler ◽

Ying Lu ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Acute Leukemia ◽

Cell Transplantation ◽

Low Dose ◽

Pediatric Patients ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Hematopoietic Stem

Abstract Introduction High dose chemotherapy with or without radiation followed by hematopoietic stem cell transplantation (HSCT) is standard therapy for pediatric patients with very high risk acute leukemia. Despite maximal therapy, a significant number of these patients will relapse after HSCT (Bitan Blood 2014; Tracey BBMT 2013). The hypomethylating agent azacitidine has immunomodulatory activity at a low dose and may augment anti-leukemic graft alloreactivity when used after HSCT (Goodyear Blood 2012; Craddock BBMT 2016). We report on the feasibility and safety of azacitidine administration following HSCT for pediatric acute leukemia. Methods Enrollment of pediatric patients with acute leukemia in this phase I/ II prospective study (NCT02458235) started in May of 2015 and is ongoing. Intravenous azacitidine (160 mg/m2 divided over 4 days) was administered as early as Day +30 post-HSCT for up to 7 consecutive cycles. Patients underwent myeloablative conditioning regimens according to standard protocols using a backbone of either total body irradiation or busulfan, combined with one or more of the following: thiotepa, melphalan, fludarabine, and clofarabine. Any stem cell source was allowed. Azacitidine was combined with immunomodulatory interventions such as fast withdrawal of immunosuppression and donor lymphocyte infusion if indicated, based on mixed chimerism or persistent minimal residual disease. Study subjects were monitored for azacitidine toxicity via weekly blood tests (complete blood count and biochemistry panel). Lymphocyte subsets and function were tested prior to each azacitidine cycle. Azacitidine was not administered in cases of hepatic injury as measured by elevated transaminases >5 times upper limit of normal; cytopenias requiring regular blood product transfusions or growth factor support; vital sign instability; or at the discretion of the treating physician. If tolerated, azacitidine was continued in 6-weekly cycles for a maximum of 7 cycles. Results Of 11 patients registered on the study with intent to receive azacitidine, 6 received the first dose of azacitidine prior to Day +60 (ranging from day +38 to day +60). An additional 4 patients received the first dose of azacitidine when clinically stable (ranging from Day +67 to Day +95), while 1 patient did not receive the drug due to early death from infection following HCT. Following azacitidine administration, thrombocytopenia requiring transfusion (10 x 109/L) was observed in 1 patient; anemia requiring transfusion (Hb 6.4 g/dL) in 1 patient; and transient elevated LFT's > 5 times the upper normal limit in 4 patients which resolved spontaneously. An additional 2 patients developed sustained elevation in LFT's related to GVHD and no further azacitidine was administered. No patients required delays in subsequent cycles by > 4 weeks due to side effects of azacitidine. One patient developed VOD at Day +50 post-HSCT following azacitidine administration and did not receive further cycles of azacitidine. One patient developed Grade 4 acute GVHD and went on to develop severe chronic GVHD. An additional 3 patients developed Grade 2-3 acute GVHD which resolved in two of these. At a median follow up of 8 months, 2 patients had experienced leukemia relapse. All of the 6 patients followed for >6 months achieved T cell reconstitution with CD4 and CD8 counts >200 (Figure 1). Five of these 6 patients achieved CD3 phytohemagglutinin response > 50% of control; one patient did not due to treatment for chronic GVHD. Conclusion Low-dose azacitidine administration is feasible in the post-HSCT setting for pediatric patients with acute leukemia. No severe toxicity directly attributable to azacitidine was observed; the role of azacitidine in the development of late VOD in one patient is unclear. Although transient liver abnormalities and cytopenias were common, low-dose azacitidine appears to be safe in the immediate post-transplant period. Further studies of immunomodulatory effects of azacitidine are required in order to optimize post-HSCT graft alloreactivity and minimize the risk of post-HSCT relapse. Disclosures No relevant conflicts of interest to declare.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽

10.1182/blood-2019-122762 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3320-3320

Author(s):

Amy E. DeZern ◽

Marianna Zahurak ◽

Javier Bolanos-Meade ◽

Richard J. Jones

Keyword(s):

Graft Failure ◽

Acute Gvhd ◽

Risk Index ◽

Chronic Gvhd ◽

Prospective Trial ◽

Stopping Rules ◽

High Dose ◽

Gvhd Prophylaxis ◽

Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

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Second Allogeneic Hematopoietic Stem Cell Transplantation for Post-Transplant Relapsed Acute Leukemia in Children - an EBMT PDWP Retrospective Study

Blood ◽

10.1182/blood.v130.suppl_1.912.912 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 912-912

Author(s):

Isaac Yaniv ◽

Aviva C. Krauss ◽

Eric Beohou ◽

Arnaud Dalissier ◽

Selim Corbacioglu ◽

...

Keyword(s):

Prognostic Factors ◽

Prognostic Factor ◽

Acute Leukemia ◽

Pediatric Patients ◽

Multivariate Analyses ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Entire Cohort

Abstract Introduction Using the EBMT registry, we retrospectively analyzed outcomes for 373 pediatric patients who underwent second allogeneic transplant for relapsed acute leukemia at 120 centers in 32 countries, between the years 2004 and 2013, in an attempt to assess relapse, survival, GVHD and other outcomes, as well as identify factors correlating with prognosis in this cohort of patients. To our knowledge, this is the largest analysis of pediatric patients undergoing second allogeneic HSCT for relapsed acute leukemia to date. This allowed for an independent analysis of each disease, including 214 patients with ALL and 159 with AML. Patients and Methods Centers received a questionnaire completing data already available in the ProMISe database on patients between 0-18 years of age treated between 2004 and 2013. Results A total of 387 patients received a second SCT after relapse. 373 have been included in the analysis, 214 for ALL and 159 for AML. Detailed data were available for 201 patients from 48 centers; for the remainder, analysis was based on the registry. For the entire cohort overall survival (OS) at 2 and 5 years were 38% and 29%, and leukemia free survival (LFS) 30% and 25% respectively. ALL: With a median follow up from 2nd SCT of 36.4 months, OS at 1 and 5 years were 47% and 28% respectively. LFS was 39% and 28% respectively. NRM at 2 years was 22%. In multivariate analyses favorable prognostic factors for both OS and LFS were: CR prior to 2nd SCT (p=0.0001), interval > 12 months between transplants (p=0.0007), use of myeloablative conditioning (p=0.039) and the presence of cGvHD after the first SCT (p=0.0001). Good prognostic factor for low NRM was interval of more than 12 months between transplants (p=0.0002). AML: With a median follow up from 2nd SCT of 50 months, OS at 1 and 5 years were 44% and 15% respectively. LFS was 28% and 15% respectively. NRM at 2 years was 18%. In multivariate analyses, favorable prognostic factors for OS as well as LFS were: CR prior to 2nd SCT (p=0.031;0.044 respectively), interval > 6 months between transplants (p=0.0003;0.0001 respectively), and having cGvHD after the first SCT (p=0.0001). Most patients experience disease relapse or NRM within the first year after their second transplant. This observation seems to be more consistent in patients transplanted for ALL, with more changes over time in patients with AML. For ALL in particular, the 2-year incidences of relapse, NRM and LFS were not different from those at 5-years. Even in the relapse setting, survival rates for patients with ALL remain superior to patients with AML, consistent with the prognostic differences at diagnosis. Our findings, consistent for the AML and ALL subgroups, suggest that cGHVD prior to second HSCT is associated with better outcome. The identification of cGHVD prior to second transplant has not been heretofore described as a favorable prognostic factor. This strong correlation merits further study, specifically as to the underlying biology for this association. Conclusion Children with relapsed acute leukemias have a substantial chance to become long term survivors following a second SCT. CR prior to second SCT, longer interval between transplants and the presence of cGvHD after the first transplant, are favorable prognostic factors for ALL and AML. Our findings may help physicians in discussing the risk-benefit of a second transplant. These results are particularly relevant in an era where an explosion of new therapies, specifically targeted therapies and those that modulate the immune response, behoove us to carefully identify subpopulations of patients for whom specific therapies are appropriate. Novel approaches are needed to minimize relapse risk as well as short and long term morbidity in these pediatric patients while considering a second SCT for relapsed acute leukemia. Disclosures Corbacioglu: Jazz Pharmaceuticals: Consultancy, Honoraria. Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

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Bone marrow transplantation in Fanconi anemia using matched sibling donors

Blood ◽

10.1182/blood.v84.6.2050.2050 ◽

1994 ◽

Vol 84 (6) ◽

pp. 2050-2054 ◽

Cited By ~ 57

Author(s):

M Kohli-Kumar ◽

C Morris ◽

C DeLaat ◽

J Sambrano ◽

M Masterson ◽

...

Keyword(s):

Bone Marrow ◽

Fanconi Anemia ◽

Low Dose ◽

Chronic Gvhd ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Feasible Option ◽

Matched Sibling ◽

Low Incidence

Abstract Eighteen patients with Fanconi anemia (FA) with evidence of bone marrow (BM) aplasia underwent allogenic BM transplants (BMT) from matched sibling donors (MSD). Median age at BMT was 7.6 years. Conditioning consisted of low-dose cyclophosphamide (CY; 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI; 400 cGy). Graft-versus-host disease (GVHD) prophylaxis included cyclosporin A and prednisone. In addition antithymocyte globulin (ATG) was administered in the pretransplant period to promote engraftment and in the posttransplant period for additional GVHD prophylaxis. Engraftment occurred rapidly (median, 12 days for an absolute neutrophil count > or = 0.5 x 10(9)/L; median, 22 days for platelet count > or = 50 x 10(9)/L). Seventeen patients have sustained engraftment and are transfusion-independent, with Lansky scores of 100% at median follow-up of 27 months. One patient developed graft failure 4 months after initial engraftment and required a second BM infusion. None of the patients developed acute GVHD; 3 patients (16%) developed chronic GVHD. BMT is a feasible option for FA patients having an MSD and should be performed at a young age and early in the course of the disease, before the development of complications. We believe the addition of ATG to the transplant regimen of low-dose CY, TAI, and cyclosporin was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.

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