Treosulfan-Based Preparative Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Children with Increased Risk of Conventional Regimen Toxicity.

Abstract It was investigated whether in children demonstrating high risk of toxicity related to conventional preparative regimens (prep-reg) for allo-HSCT, the prep-reg based on Treosulfan (TREO) (Feit, Rastrup-Andersen, 1970) enables to avoid severe toxic complications without increased incidence of graft failure and/or relapse. From July 2000 to April 2005 the TREO-based prep-reg was used prior to allo-HSCT in 43 children with increased risk of severe Busulfan- and FTBI-based regimens related toxicity (RRT) and/or non-compliance. In 37 patients (pts) allo-HSCT was performed for, usually advanced, hematological malignancy, incl. 19 pts (1–17 yrs, med. 9) transplanted from MSD for ALL (n=8), AML (n=7), LCH (n=2), MDS (n=1) and NHL (n=1), and 18 pts (0.5–17 yrs, med. 9.5) from MUD for AML (n=7), ALL (n=4), CMML (n=3), NHL (n=2) and CML (n=2). Six pts (0.5–12 yrs, med. 6) underwent HSCT for congenital disorder, i.e. 5 from MSD for ALD (n=2), WAS (n=2) and B-DA (n=1), and one from MUD for osteopetrosis. Total of 24 pts were transplanted from MSD and 19 from MUD. TREO (3x10 g/m2, n=22; 3x12 g/m2, n=19; 3x14 g/m2, n=2) was given i.v. in various combination with FLUDA, CY, MEL or VP-16 acc. to diagnosis, risk factors of RRT and/or regimen used for previous HSCT. Prior MUD-HSCT and all pts with congenital disorders received ATG (n=18) or Campath (n=3). RRT was graded acc. to Bearman (1988). In 21 out of 43 pts (incl. all 6 with congenital diseases) no features of RRT occured, I° in 13, II° in 5, and III° in 4 (mucositis). Engraftment was achieved in all pts, except one transplanted from MUD for CML with low dose of CD34 cell (1.7x106/kg). Acute GvHD II–III° occurred in 9/24 pts after MSD-HSCT and in 10/19 after MUD-HSCT, chronic GvHD in 4/24 post MSD-HSCT and 1/19 after MUD-HSCT. Chimerism was evaluated in 22/24 pts after MSD-HSCT and in 18/19 post MUD-HSCT. Respectively, complete donor chimerism was observed in 17/22 and 16/18 pts, mixed in 5/22 and 1/18, and autologous recovery in 1/18 after MUD-HSCT. Non-relapse deaths occurred in 6 out of 37 pts with malignancy, incl. one 40 mo. post MSD-HSCT (pulmonary aspergillosis, cGvHD), and 5 after MUD-HSCT (abdominal aorta thrombosis day+59, LPD day+63, BKV infection day+66; intracranial bleeding day+138). The 1-year non-relapse mortality was 13,5%. Relapse was diagnosed in 8/19 pts post MSD-HSCT (4xAML, 4xALL) and in 1/18 after MUD-HSCT (sAML). Out of 24 pts transplanted from MSD, 15 are alive, i.e. 10/19 with malignant disease in CCR (med. 27, 16–50 mo.) and 5/5 with congenital disorder (med. 21, 6–58 mo.). After MUD-HSCT, 12/18 pts with malignancy are alive in CCR (med. 19, 7–42 mo.) and a child with osteopetrosis (4 mo.). At 3 years from HSCT in 19 pts with malignancy transplanted from MSD the progression-free survival (PFS) was 46% and overall survival (OS) 49%, while in 18 transplanted from MUD 82% and 68%. The PFS and OS estimated for 6 pts with congenital disorders at 4 years after HSCT was 67% and 100%. Conclusions: In children with high risk of conventional regimen related toxicity the prep-reg for allo-HSCT based on TREO given at the dose of 3 x 10–12 g/m2i.v. demonstrates almost exclusively mucosal toxicity, along with sufficient myeloablative and immunosuppressive effects. Its anti-leukemic effect is at least comparable with that one of Busulfan-based regimens.

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Tandem Autologous Stem Cell Transplants (auto-auto) with or without Maintenance Therapy Versus Single Autologous Transplant Followed by HLA-Matched Sibling Non- Myeloablative Allogeneic Stem Cell Transplant (auto-allo) for Patients (pts) with High Risk (HR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) 0102 Trial

Blood ◽

10.1182/blood.v116.21.526.526 ◽

2010 ◽

Vol 116 (21) ◽

pp. 526-526 ◽

Cited By ~ 6

Author(s):

Edward A Stadtmauer ◽

Amrita Krishnan ◽

Marcelo C Pasquini ◽

Marian Ewell ◽

Edwin P Alyea ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplant ◽

Chronic Gvhd ◽

Secondary Analysis ◽

Progression Free Survival ◽

Phase Iii ◽

Cell Transplant ◽

Primary Analysis ◽

Hematopoietic Stem

Abstract Abstract 526 The prognosis of patients with high-risk myeloma (HR MM) continues to be dismal, despite the early incorporation of novel agents. Early phase trials of allogeneic hematopoietic stem cell transplant (alloHCT) suggest the possibility of an immunologic graft-versus-myeloma effect that might favorably affect survival. Less toxic reduced-intensity HCT preparative regimens now allow more widespread use of alloHCT in the MM population. BMT CTN 0102 is a phase III multicenter clinical trial that biologically assigned patients to either melphalan 200mg/m2 (MEL 200) auto-auto without (obs) or with 1 year of thalidomide and dexamethosone (ThalDex), or an auto-allo approach using MEL 200 followed by alloHCT using 2 Gy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine and mycophenolate mofetil. Patients were stratified by biological prognostic factors that were considered to be high risk at the time of the trial design: chromosome 13 deletions by metaphase karyotype and beta-2 microglobulin ≥4 mg/dl. The primary endpoint was 3-year progression free survival (PFS). Between December 2003 and March 2007, 710 patients from 43 US centers were enrolled, and 85 fulfilled the criteria of HR MM. Among them, 48 were assigned to auto-auto (24 Thal-Dex and 24 obs) and 37 to auto-allo. Groups differed in age (median 57 y and 51y, p=0.02) but were otherwise balanced. Compliance with second transplant was 65% for auto-auto and 78% for auto-allo. Compliance with ThalDex was poor, so the two auto-auto arms were pooled for the primary analysis. Three-year PFS was 33% (95% Confidence Interval (CI), 22–50%) and 40% (95% CI, 27–60%, p=0.74) and 3-year OS was 67% (95% CI, 54–82%) and 59% (95% CI, 49–78%, p=0.46) for auto-auto and auto-allo, respectively. Corresponding probabilities for 3-year progression/relapse was 53% and 33% (p=0.09), and 3 year treatment-related mortality was 8% and 20% (p=0.3). Among auto-allo patients, probabilities of grade 3–4 acute and chronic GVHD were 9% and 48%, respectively. Among the 59 (31 auto-auto, 28 auto-allo) patients who received second transplant, 3 year PFS was 35% and 46% (p=0.6). Disease response at day 56 after second transplant was 57% for very good partial response (VGPR) or better and 37% for complete response (CR) and near CR (nCR) in the auto-auto group; and 48% (VGPR or better) and 41% (CR+nCR) in the auto-allo group. In conclusion, this planned secondary analysis of a cohort of HR MM patients demonstrated equivalent 3-year PFS and OS for auto-auto and auto-allo in both intention-to-treat and as-treated analyses. However, trends in late PFS and time to progression/relapse suggest further follow-up is needed before final conclusions regarding the utility of auto-allo in this HR cohort can be made. Finally, this study shows the feasibility of an alloHCT approach for HR MM patients and may serve as a platform for future studies seeking to enhance graft-versus-myeloma effects. Disclosures: Stadtmauer: Celgene: Speakers Bureau. Krishnan:Celgene: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau.

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Characteristics and Outcome of Therapy-Related MDS Developing after Primary Cancer in Children.

Blood ◽

10.1182/blood.v106.11.2514.2514 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2514-2514

Author(s):

R. Ammann ◽

M. Zecca ◽

D. Betts ◽

J. Harbott ◽

M. Trebo ◽

...

Keyword(s):

Median Time ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Platinum Compounds ◽

Hematopoietic Stem ◽

Monosomy 7 ◽

Prior Therapy ◽

Increased Risk ◽

Preparative Regimen

Abstract Treatment-related myelodysplastic syndrome (tMDS) is a serious complication of therapy of childhood cancer. Here we report on 59 patients (pts) (35 males, 24 females) with tMDS enrolled in the prospective study EWOG-MDS 98. Prior malignancy was ALL in 21 pts, AML in 5, lymphoma in 6, CNS tumors in 12, and other solid tumors in 15. Median age at diagnosis of tMDS was 11.2 yrs (range 1.2 – 23.2), and median time between first malignancy and tMDS 3.3 yrs (range 0.5 – 11.1). Disease was classified as refractory cytopenia in 15 pts, RAEB in 30 and RAEB-T in 14. Of the 47 pts with cytogenetic analysis at diagnosis, 77% had an abnormal karyotype, including 38% that were complex. Monosomy 7 with or without other abnormalities was detected in 38%. Progression of disease was noted in 26 of 52 evaluable pts at a median time of 2.5 mo (range 0.3 – 16) from diagnosis; the cumulative incidence of progression being 74%. After a median follow-up time of 20 mo (range 3–69) 28 pts are alive with an estimated 5-year overall survival of 32% (95% CI 20 – 51). No child survived beyond 15 mo from diagnosis without receiving allogeneic hematopoietic stem cell transplantation (HSCT). HSCT was performed in 45 pts. Source of stem cells was bone marrow in 24 pts, peripheral blood in 20 and cord blood in 1. The donor was an HLA-identical relative (MFD) in 18 cases, while 26 pts were transplanted from an HLA-matched or 1-antigen/allele disparate unrelated donor (UD) and 1 pt from a 2-antigen disparate parent. Preparative regimen included busulfan 16 mg/kg, cyclophosphamide 120 mg/kg and melphalan 140 mg/m2 in 32 pts. Prophylaxis of GVHD generally consisted of cyclosporine-A for MFD, combined with methotrexate and ALG for UD. Two patients had graft failure. The cumulative incidence of grade II–IV acute GVHD and chronic GVHD were 32% (95% CI 28 – 37) and 24% (95% CI 19 – 28), respectively. Twelve pts suffered transplant-related mortality (TRM), the cumulative incidence of TRM in pts transplanted from a MFD or UD being 12% and 39%, respectively (P=0.058). Prior therapy with platinum compounds was an independent predictor of an increased risk of TRM. Fifteen pts relapsed at a median time of 9 mo (range 2 – 29) after HSCT, the 5-year cumulative incidence of relapse being 44% (95% CI 21 – 66). A WBC > 4 G/L at diagnosis predicted a higher risk of relapse. Twenty-one of the 45 pts transplanted are alive and 19 are disease-free. The estimated 5-year EFS after HSCT was 27% (95% CI 15 – 47). Prior therapy with platinum compounds, a WBC > 4 G/L at diagnosis, and a female donor predicted inferior EFS, while HSCT from an UD versus MFD resulted in similar outcome (5-year EFS, 21% and 39%, respectively). AML-type therapy prior to HSCT did not improve survival. Innovative stragegies for improving the outcome of these patients are warranted.

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A Phase II Study of Decitabine Followed By Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Patients with Myeloid Malignancies

Blood ◽

10.1182/blood-2018-99-112670 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2107-2107

Author(s):

Christopher R. D'Angelo ◽

Aric C. Hall ◽

Kyungmann Kim ◽

Ryan J. Mattison ◽

Walter L. Longo ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Chronic Gvhd ◽

Infectious Complications ◽

Myeloablative Conditioning ◽

Hematopoietic Stem ◽

Post Transplant ◽

Risk Patients

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for myelodysplastic syndrome (MDS) and high-risk acute myeloid leukemia (AML). Patients with high-risk disease have a markedly increased risk of relapse and death following transplant (Armand et al, Blood, 2014). Those who remain disease-free are at risk of severe morbidity from graft-versus- host-disease (GvHD). These issues highlight the importance of improved allo-HSCT platforms designed to reduce relapse rate without increasing risk of GvHD. Decitabine has minimal non-hematologic toxicity and proven efficacy in myeloid diseases (Blum et al, PNAS, 2010). Use of post-transplant cyclophosphamide has demonstrated improved rates of GvHD following allo-HSCT using haplo-identical donors (Bashey et al, JCO, 2013). No studies have reported on outcomes in patients undergoing decitabine immediately prior to transplantation followed by post-transplant cyclophosphamide (PTCy). We hypothesized that the combination of decitabine induction prior to transplant and PTCy would be safe and result in improved disease control with low rates of GVHD, translating into improved survival in a high-risk transplant cohort. Methods In this single-arm, single institution trial, eligible patients received 10 days of IV decitabine at 20mg/m2 no sooner than 24 days and no later than 17 days prior to conditioning. Myeloablative conditioning included fludarabine (50mg/m2 day-5-2), busulfan (IV 3.2mg/kg/day -5-2), and 4 Gy total body irradiation on day -1. Patients above age 65 received a 25% busulfan dose reduction. Patients received a fully or partially matched related bone marrow graft on day 0. GvHD prophylaxis included 50mg/kg of IV cyclophosphamide on day +3-4. Patients with fully matched donors received only PTCy while those with partially matched donors also received mycophenolate mofetil through day +35 and tacrolimus through day +180. Results We enrolled 20 patients, fifteen patients with AML and 5 with MDS. The cohort had a median age of 64 (29-73) and was predominantly male (14/20, 70%). Eight (40%) patients scored as high risk by the HSCT comorbidity index. Eighteen patients (90%) had a high or very high-risk score by the refined disease risk index. All patients received decitabine and 18/20 (90%) underwent transplantation; 2 patients did not receive a transplant due to infectious complications. The majority of patients received a haplo-identical graft (13/18, 72%), and the remaining 5 received a matched related graft. Outcomes are reported in table 2 and figure 1. There were no engraftment failures. Five patients, 3 MDS and 2 AML, are long-term survivors with median follow-up over 3 years. One patient developed donor derived MDS and required a second transplant. Most transplanted patients (13/18, 72%) survived to day 100 with a median post-transplant survival of 138 days. There were 15 deaths on study with the majority due to underlying disease. Six patients (6/20, 30%) died of infectious complications or did not receive a transplant due to infection. Incidence of grade 3-4 acute GvHD was low among those surviving at least 40 days from transplant (3/17, 17%). There were also low rates of chronic GvHD among the 12 patients alive without ongoing GvHD at day 100 (2/12, 17%). Conclusions Decitabine induction followed by myeloablative conditioning in this high-risk population resulted in a high treatment related mortality of 40%. Still, outcomes fell into an expected range for high-risk myeloid disease in an elderly and comorbid population. Based on expected outcomes for high-risk patients from the literature (Armand et al, Blood, 2014), decitabine did not markedly improve overall survival outcomes, recognizing that no direct comparisons are available in our limited study population. Decitabine may increase the risk of peri-transplant infections by contributing to a cumulative immunologic insult combined with disease-related immunosuppression and transplant-related toxicity, highlighting the importance of strict vigilance for infections within this setting. Diligent monitoring may improve infectious outcomes as shown in the second half of the cohort; only two out of the latter 10 patients on protocol died of treatment related complications. There were no cases of engraftment failure. Rates of acute and chronic GvHD using a PTCy platform were low and support other studies reporting this benefit. Disclosures No relevant conflicts of interest to declare.

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Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants

Blood ◽

10.1182/blood.v95.12.3683 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3683-3686 ◽

Cited By ~ 99

Author(s):

Samar Kulkarni ◽

Ray Powles ◽

Jennie Treleaven ◽

Unell Riley ◽

Seema Singhal ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Pneumococcal Infection ◽

Pneumococcal Infections ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Increased Risk ◽

Penicillin Prophylaxis

Abstract Incidences of and risk factors for Streptococcus pneumoniaesepsis (SPS) after hematopoietic stem cell transplantation were analyzed in 1329 patients treated at a single center between 1973 and 1997. SPS developed in 31 patients a median of 10 months after transplantation (range, 3 to 187 months). The infection was fatal in 7 patients. The probability of SPS developing at 5 and 10 years was 4% and 6%, respectively. Age, sex, diagnosis, and graft versus host disease (GVHD) prophylaxis did not influence the development of SPS. Allogeneic transplantation (10-year probability, 7% vs 3% for nonallogeneic transplants; P = .03) and chronic GVHD (10-year probability, 14% vs 4%; P = .002) were associated with significantly higher risk for SPS. All the episodes of SPS were seen in patients who had undergone allograft or total body irradiation (TBI) (31 of 1202 vs 0 of 127;P = .07). Eight patients were taking regular penicillin prophylaxis at the time of SPS, whereas 23 were not taking any prophylaxis. None of the 7 patients with fatal infections was taking prophylaxis for Pneumococcus. Pneumococcal bacteremia was associated with higher incidences of mortality (6 of 15 vs 1 of 16;P = .04). We conclude that there is a significant long-term risk for pneumococcal infection in patients who have undergone allograft transplantation, especially those with chronic GVHD. Patients who have undergone autograft transplantation after TBI-containing regimens also appear to be at increased risk. These patients should receive lifelong pneumococcus prophylaxis. Consistent with increasing resistance to penicillin, penicillin prophylaxis does not universally prevent SPS, though it may protect against fatal infections. Further studies are required to determine the optimum prophylactic strategy in patients at risk.

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Allo-HSCT in transplant-naïve patients with Hodgkin lymphoma: a single-arm, multicenter study

Blood Advances ◽

10.1182/bloodadvances.2019001016 ◽

2019 ◽

Vol 3 (24) ◽

pp. 4264-4270 ◽

Cited By ~ 1

Author(s):

Emma Das-Gupta ◽

Kirsty J. Thomson ◽

Adrian J. C. Bloor ◽

Andrew D. Clark ◽

Stephen Mackinnon ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Complete Response ◽

Primary Objective ◽

Mixed Chimerism ◽

Hematopoietic Stem ◽

Positron Emission ◽

Computed Tomography Scanning ◽

Unrelated Donors

Abstract We evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180.

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Adverse events in second- and third-line treatments for acute and chronic graft-versus-host disease: systematic review

Therapeutic Advances in Hematology ◽

10.1177/2040620720977039 ◽

2020 ◽

Vol 11 ◽

pp. 204062072097703

Author(s):

Vladica M. Velickovic ◽

Emily McIlwaine ◽

Rongrong Zhang ◽

Tim Spelman

Keyword(s):

Systematic Review ◽

Adverse Events ◽

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Host Disease ◽

Pharmaceutical Management ◽

Graft Versus Host ◽

Increased Risk ◽

Third Line

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with an increased risk of graft- versus-host disease (GvHD), a strong prognostic predictor of early mortality within the first 2 years following allo-HSCT. The objective of this study was to describe the harm outcomes reported among patients receiving second- and third-line treatment as part of the management for GvHD via a systematic literature review. Methods: A total of 34 studies met the systematic review inclusion criteria, reporting adverse events (AEs) across 12 different second- and third-line therapies. Results: A total of 14 studies reported AEs across nine different therapies used in the treatment of acute GvHD (aGvHD), 17 studies reported AEs of eight different treatments for chronic GvHD (cGvHD) and 3 reported a mixed population. Infections were the AE reported most widely, followed by haematologic events and laboratory abnormalities. Reported infections per patient were lower under extracorporeal photopheresis (ECP) for aGvHD (0.267 infections per patient over 6 months) relative to any of the therapies studied (ranging from 0.853 infections per patient per 6 months under etanercept up to 1.998 infections per patient on inolimomab). Conclusion: The reported incidence of infectious AEs in aGvHD and grade 3–5 AEs in cGvHD was lower on ECP compared with pharmaceutical management.

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Impact of Targeted Immunotherapies and Novel Cytogenetic and Clinical Risk Groups on Outcome after Allogeneic Hematopoietic Stem Cell Transplant (AlloHCT) for Acute Lymphoblastic Leukemia (ALL): The Mayo Clinic Cohort

Blood ◽

10.1182/blood-2019-122068 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2588-2588

Author(s):

Zaid Abdel Rahman ◽

Michael G. Heckman ◽

Kevin C. Miller ◽

Patricia Greipp ◽

Matthew R Spiegel ◽

...

Keyword(s):

High Risk ◽

Tyrosine Kinase ◽

Targeted Therapies ◽

Mayo Clinic ◽

Lower Risk ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Risk Groups ◽

Increased Risk ◽

The Impact

Introduction Novel high-risk groups have been identified in adult ALL, including secondary (sALL) and Philadelphia-like ALL (Ph-like, based on CRLF2, IgH, ABL2, JAK2 and other tyrosine kinase translocations), and those with minimal residual disease >0.1% (MRD+) after induction therapy. Novel targeted therapies are now routinely incorporated into 1st line regimens, including tyrosine kinase inhibitors (BCR-ABL1-pos), rituximab (CD20+) and blinatumomab (Blina) for MRD+. The impact of these novel high risk groups and therapies after alloHCT is unknown; therefore, we evaluated their impact on overall survival (OS), relapse rate (REL), non-relapse mortality (NRM) and acute and chronic GVHD. Methods We evaluated pts receiving 1st Allo-HCT for ALL at Mayo Clinic (Rochester, Phoenix, and Jacksonville) from 2008-2018 for outcomes of interest, specifically the impact of novel therapies and risk groups. Associations of patient factors with outcomes were examined using univariable (UVA) and multivariable (MVA) Cox proportional hazards regression models, where the cause-specific hazard of the given outcome was modeled to account for the competing risk of death. Results We identified 261 consecutive AlloHCT recipients during the study period. Median age at transplant was 48 years (18-72) and 147 (56.3%) were male. The median comorbidity (HCT-CI) score was 2 (0-8). 213 pts (81.6%) had B-lineage ALL, of which 85 (32.6%) were BCR-ABL-pos, 17 (6.5%) Ph-like (identified by FISH), 16 (6.1%) hypoploidy/near triploidy (Hy/Tri), and 67 (25.7%) pre-B ALL NOS. The remaining 48 (18.4%) had T-ALL. 30 pts (11.5%) had sALL (i.e. prior chemo/radiotherapy for another malignancy). HyperCVAD was the most common 1st line regimen (68.2%). 243 (93.1%) pts achieved Complete Remission (CR1) after induction therapy, and 203 (77.8%) were in CR1 at the time of alloHCT. Blina was administered for MRD+ in 14 pts (5.4%), and for relapsed/refractory ALL (R/R) in 13 (27% of R/R pts), 7 of whom received Blina as initial therapy for R/R. Donors were matched unrelated in 149 (57.1%), matched related in 98 (37.5%), and haploidentical in 14 (5.4%). Peripheral blood (PB) grafts were used in 233 (89.3%). 103 (54.5%) were donor:recipient (D:R) sex-matched, and 86 D:R mismatched [47 (24.9%) M:F; and 39 (20.6%) F:M]. Myeloablative conditioning was used for the majority (78.5%) mostly with Cy/TBI (60.5%). Standard GVHD prophylaxis regimens were used. Outcomes Median follow-up after transplant was 22.4 months (0.5-135), and 51 (19.5%) had REL. The 1, 2 and 5-year survival rates were 71.9%, 64.9%, and 54.1%, respectively (Figure 1). Acute GVHD developed in 144 (55.2%) and chronic GVHD in 100 (38.3%). Ph-like ALL, Blina for MRD+, Blina for R/R, sALL and CD20-pos had no independent impact on OS. In contrast, age>60, Hy/Tri, and >CR1 at alloHCT were associated with worse OS in UVA, however, in MVA only pre-B ALL NOS was associated with better OS. Female:male D:R status was associated with inferior OS. Blina for R/R disease was associated with increased risk of REL in UVA [HR 5.26 95% CI (1.33, 20.00), p=0.017], whereas other novel high risk groups had no impact on REL. In contrast, T-ALL, Hy/Tri and >CR1 at AlloHCT were associated with increased REL in UVA, but only T-ALL and Hy/Tri continued to predict for increased REL in MVA. Secondary ALL was associated with increased NRM in UVA [HR 1.96 95% CI (1.07, 3.57), p=0.028], whereas other novel high risk groups had no impact on NRM. In contrast, age>60, >CR1 at AlloHCT and D:R sex mismatch were associated with higher NRM in UVA, but only sex mismatch and >CR1 at AlloHCT were associated with higher NRM in MVA. TBI use was associated with higher risk of acute GvHD (p=0.008) and ATG use with lower risk chronic GVHD (p<0.001). Similarly non-PB grafts were associated with a lower risk of chronic GVHD (p=0.005). Results for OS, REL, NRM, acute and chronic GVHD analysis are shown in Table 1. Conclusion Novel high risk groups (CD20+, Ph-like and sALL) do not appear to adversely impact OS after alloHCT, although sALL was associated with increased risk of NRM. Interestingly, pre-B-ALL NOS appear to be associated with favorable OS. Novel targeted therapies also do not independently predict outcome, with the exception of Blina for R/R ALL which may be associated with REL after subsequent alloHCT (a subgroup for whom novel maintenance strategies should be explored). Our analysis highlights the importance of allo-HCT for novel high risk ALL subgroups. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Foran:Agios: Honoraria, Research Funding.

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Efficacy of Reduced Intensity Conditioning (RIC) with FLU-BU-ATG and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Pediatric ALL.

Blood ◽

10.1182/blood.v104.11.2314.2314 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2314-2314 ◽

Cited By ~ 5

Author(s):

Reggie Duerst ◽

David Jacobsohn ◽

William T. Tse ◽

Morris Kletzel

Keyword(s):

Stem Cell ◽

High Risk ◽

Chronic Gvhd ◽

High Dose ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Pediatric All ◽

Very High ◽

Reduced Intensity

Abstract Reduced Intensity Conditioning (RIC) regimens prior to allogeneic HSCT have gained acceptance in the treatment of adults with myelodysplasia, leukemia and multiple myeloma. RIC reduces the risk for regimen related morbidity and mortality enabling patients with pre-existing medical conditions that would have been precluded from allogeneic HSCT to attempt a curative approach. The resilience of pediatric patients (pts) following high-dose conditioning regimens and the concern that ALL cells are inherently more resistant to a graft-vs-leukemia effect have limited accrual of pediatric ALL pts to RIC protocols despite the potential benefit for reduced long-term morbidity. We report the experience of 10 pediatric ALL pts (6 M, 4 F, median age 9.5 years) treated for recurrent ALL with RIC and allogeneic HSCT. A uniform RIC regimen comprised of fludarabine, 30 mg/m2 for 6 consecutive days (days −10 through −5), followed by intravenous busulfan, 0.8 – 1 mg/kg for 8 doses or targeted AUC 4000 μMol*min for 2 doses (days −5 and −4) and equine ATG, 40 mg/kg or rabbit ATG, 2 mg/kg for 4 days (days −4 through −1) was administered. Pts with prior CNS involvement received whole brain (2400 cGy) and spinal (1800 cGy) irradiation immediately prior to the RIC. Stem cell sources included 7 unrelated donors and 3 matched sibs. 9 of 10 stem cell donations were peripheral blood stem cells (PBSC). The median cell doses infused were 6.5 x 108 MNC/kg and 4.2 x 106 CD34+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CsA) alone in 5 patients, CsA and mycophenolate mofetil in 5 pts. Growth factor support was not used. Each of the pts had at least two very high-risk features--prior HSCT (n = 6), CR > 3/refractory disease (8), prior CNS disease (6), Ph+ (2), pre-exisiting neurologic (1) or cardiac (1) dysfunction or aspergillous infection (1). Full donor chimerism was achieved in 9 of 10 with a median time to reach an ANC >500/μl of 16 days (range 11–62) and an unsupported platelet count > 20,000/μl was achieved in 8 of 10 at a median of 25 days (15–67). 2 pts developed Gr IV acute GVHD, 2 of 5 pts surviving more than 100 days developed chronic GVHD. Only 3 patients have relapsed: 1 refractory T-ALL pt recurred day +27 and 2 Ph+ pts had a molecular relapse day +61 and +196. The latter pt is in subsequent continuous molecular remission for over 1 year on imatinib therapy. 6 pts have died, 5 in the first 100 days of HSCT from complications of GVHD (2), relapse (1), pulmonary failure (in 1 pt S/p 3 prior allogeneic HSCT) and PTLD (1). 1 pt succumbed from complications of chronic GVHD day +756. The RIC regimen and supportive care are primarily an outpatient experience. During the first 30 days post HSCT, pts spent an average of only 9 days in hospital (23 of the first 100 days). Despite very high-risk features, 4 of 10 pts survive (3 CCR) at a median of 500 days post HSCT. Thus, RIC and allogeneic HSCT also offers promise for efficacy in pediatric ALL.

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A Pilot Study for Haploidentical Transplant Using a Chemotherapy only Preparative Regimen eith T-Cell Depleted Haploidentical Transplant and Intensive Antibiotic Prophylaxis To Treat Advanced Leukemia Patients (pts).

Blood ◽

10.1182/blood.v104.11.5184.5184 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5184-5184

Author(s):

James L. Gajewski ◽

Rima Saliba ◽

John D. McMannis ◽

Elizabeth J. Shpall ◽

Cindy Ippoliti ◽

...

Keyword(s):

Body Weight ◽

T Cell ◽

Chronic Gvhd ◽

Progression Free Survival ◽

Infectious Complications ◽

Multiple Organ ◽

High Rate ◽

Cd34 Cells ◽

Preparative Regimen ◽

One Year

Abstract We present preliminary data of haploidentical transplant for 12 patients (pts) with relapse of refractory acute leukemia using a chemotherapy only preparative regimen of 140 mg/m2 Melphalan on day −8; 10 mg/kg Thiotepa on day −7; 160 mg/m2 Fludarabine on days −6, −5, −4, −3; 1.5 mg/kg of rabbit ATG/day days −6, −5, −4, −3 and T-cell depleted peripheral blood progenitor cells, processed using the CliniMACS® device. All products had <1 x 104 CD3+ T-cells/kg recipient body weight and needed a minimum of 5 x 106 CD34+ cells/kg but preferably >1 x 107 CD34+ cells/kg recipient body weight. Pts received: intensive PCP prophylaxis with bactrim and pentamidine prior to transplant and during pancytopenia; CMV prophylaxis with valcyte during the BMT prep and foscarnet while pancytopenic; and with ambisone for fungus. The last 4 pts enrolled were treated with cancidas prophylactically instead of ambisome. 10 of 12 pts engrafted (83%). 2 pts had protocol deviations and primary graft failure - 1 survived disease free and 1 relapsed. Median time to engraftment was 14 days (range, 9–26) to 500 neutrophils and 13 days to platelets 20,000 (range, 10–25). Among engrafting patients, two died within 100 days due to disease progression and multiple organ failure. Six-month overall survival is 50% (21–74). One year overall and progression-free survival is 33% (95% CI 10–59). 7 pts had disease relapse at a median of 10 months (range 2–13 months). Two of 10 pts who engrafted developed grade 1 acute graft-versus-host disease (GVHD) and 4/8 pts who engrafted and survived beyond day 100 had chronic GVHD. The 2 patients who engrafted and survived beyond 1 year post transplant had chronic GVHD. This report for haploidentical transplant demonstrates that a chemotherapy only preparative regimen achieved a high rate of engraftment. Infectious complications were minimal. 25% of patients survived progression free. If these results are sustained in a larger study, haploidentical transplant may offer hope of allogeneic transplant for every individual needing such therapy.

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Hematopoietic Stem Cell Transplantation (HSCT) as Curative Therapy for Fanconi Anemia (FA) Patients with Acute Leukemia or Advanced Myelodysplasia (MDS).

Blood ◽

10.1182/blood.v106.11.5464.5464 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5464-5464

Author(s):

Christopher J. Fraser ◽

John E. Wagner ◽

Margaret L. MacMillan

Keyword(s):

Acute Leukemia ◽

Hemorrhagic Cystitis ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Curative Therapy ◽

Disease Characteristics ◽

Gvhd Prophylaxis ◽

Preparative Regimen ◽

Total Body

Abstract Historically outcomes have been very poor for FA patients with advanced MDS or leukemia. It remains controversial as to whether HSCT is indicated for such patients and there is no consensus as to the optimal conditioning regimen in this setting. Traditionally, conditioning for FA patients has incorporated total body irradiation (TBI). Here, we report results of a pilot study in which we have substituted busulfan for TBI, designed for FA patients with one or more high risk features, identified following analysis of 42 previous consecutive URD FA transplants: advanced MDS or leukemia, age >18 years, or previous proven fungal or gram negative infection. Between 12/02–08/04 6 patients were enrolled, 5 with acute leukemia. Patient and disease characteristics are presented in Table 1. Conditioning consisted of busulfan (total 3.2mg/kg), cyclophosphamide (total 40mg/kg), fludarabine (total 140 mg/m2) and ATG (total dose 75mg/kg); GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. All patients received prophylactic voriconazole for one month prior to transplant. BM was T cell depleted with CD34 selection by Isolex 300i. Five out of six patients achieved neutrophil engraftment. Median time to an ANC>500 was 16 days (range: 11–20 days). One patient developed Grade I acute GVHD; no patient has developed chronic GVHD. The preparative regimen was well tolerated. Toxicities included Grade IV mucositis (n=1), VOD (n=2), hemorrhagic cystitis (n=1) and CMV pneumonia (n=1). Three patients are alive and in remission with a median follow-up of 575 days. Table 1 Age Diagnosis FANC group Remission status Donor source D+21 chimerism D+60 chimerism Vital status Patient and disease characteristics 5.9 ALL BRCA2 treated; CR 5/6 related BM 100% donor 100% donor alive d+894 21.7 AML A untreated 5/6 URD BM 99.1% donor 100% donor died resp. failure d+99 20.8 SAA A N/A 5/6 URD BM insufficient cells N/A died VOD d+24 6.6 ALL,MDS,Wilm’s BRCA2 ALL treated CR; MDS (7.5% blasts) 6/6 URD UCB 100% donor 100% donor alive d+575 7.1 AML A treated; refractory 4/6 UCB + 5/6 UCB 100% donor #2 54.7% #2; 45.3% recipient died AML relapse d+60 17.3 AML A treated; refractory 5/6 UCB x2 66.7% #1; 31.3% #2; 2% recipient 100% donor #1 alive d+423 These results suggest TBI is not required to achieve durable engraftment and leukemia control, busulfan 3.2 mg/kg is tolerable, and advanced MDS or acute leukemia does not preclude HSCT in FA patients.

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