Autologous Hematopoietic Stem Cell Transplantation (AHCT) in Patients with Chemotherapy-Sensitive, Relapsed/Refractory (CSRR) Human Immunodeficiency Virus (HIV)-Associated Lymphoma (HAL): Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0803)/AIDS Malignancy Consortium (AMC-071) Trial

Abstract Background: HIV infection is associated with increased risk of non-Hodgkin (NHL) and Hodgkin lymphoma (HL). Historically HIV-infected patients had inferior outcomes and increased treatment-related morbidity and mortality over uninfected patients. Highly active antiretroviral therapy (HAART) improved the prognosis for patients with HAL and permitted treatment identical to that in uninfected patients. The role of AHCT in HIV-infected patients, however, remains under investigation. This BMT CTN 0803/ AMC-071 trial, sponsored by the National Heart, Lung and Blood Institute and National Cancer Institute, was designed to prospectively assess overall survival (OS) after AHCT in patients with CSRR HAL. Methods : Patients with treatable HIV-1 infection, age > 15 years, adequate organ function and CSRR aggressive NHL or HL were included. Mobilization and collection followed institutional guidelines. Patients underwent AHCT using the BEAM regimen [carmustine 300 mg/m2 (day -6), etoposide 100 mg/m2 twice daily (days -5 to -2), cytarabine 100 mg/m2 (days -5 to -2), melphalan 140 mg/m2 (day -1)]. Patients received AHCT on day 0 and standard supportive care through discharge. HAART was withheld during the preparative regimen and until therapy-related GI toxicity resolved. The primary trial objective was estimation of one-year OS. Secondary objectives included lymphoma response post-transplant, progression-free survival (PFS), transplant-related mortality (TRM), infection-related complications and recovery of hematological function (RHF) post-AHCT. RHF was defined as ANC > 1500/µl, untransfused hemoglobin > 10 gm/dL and platelet > 200,000/µl. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Results : Between July 2010 and May 2013, 43 patients were enrolled; 3 progressed prior to AHCT and were excluded from analysis. Forty patients underwent AHCT (5 female, 35 male). Median age was 46.9 years (range, 22.5-62.2). Lymphoma subtypes included diffuse large B-cell lymphoma (40%), plasmablastic lymphoma (5%), Burkitt/Burkitt-like lymphoma (17.5%) and HL (37.5%). All patients received < 2 salvage regimens. Prior to transplant, 30 patients (75%) were in complete remission (CR), 8 (20%) were in partial remission (PR) and 2 (5%) had relapsed/progressive disease (RPD). Pre-HCT HIV viral load (VL) was undetectable in 31 patients (77.5%) and detectable in 9 (22.5%) with a median VL of 84 copies/mL (interquartile range [IQR], 58-234). Median CD4 count was 250.5/µL (range 39-797, IQR 175-307). All 40 patients completed BEAM and underwent HCT. At day 100 post-HCT, 39 patients were assessed for disease response (1 inevaluable due to early death): 36 (92.3%) were in CR, one (2.6%) in PR and two (5.1%) had RPD. By one-year post-HCT, 5 patients died (3 from recurrent/persistent disease, 1 from organ failure [cardiac arrest] and 1 from invasive fungal infection). Cumulative incidence of TRM was 5.2% (95% confidence interval [CI]: 0.9%-15.7%). With a median follow-up of 24 months post-AHCT, estimated probability of one-year OS was 86.6% (95% CI: 70.8%-94.2%) (Figure 1). By one-year, 5 patients relapsed post-HCT, 3 of whom subsequently died. The cumulative incidence of relapse/progression at one-year post-HCT was 12.5% (95% CI: 4.5%-24.8%). Estimated probability of one-year PFS was 82.3% (95% CI: 66.3%-91.1%) (Figure 2). Within one-year of HCT, 13 patients experienced grade 3 and 2 patients grade 4 toxicities (1 patient with mucositis and 1 patient with dyspnea/hypoxia/ cardiac arrhythmia/hypotension). Seventeen patients (42.5%) developed a total of 42 episodes of infection within one-year post-HCT, including 9 with an infection severity grade of severe. Median time to neutrophil engraftment (> 500/µl) was 11 days (range, 9-32).Median time to platelet transfusion-independent engraftment >20,000/µl was 18 days (range, 9-176); 1 patient died prior to platelet recovery. Eleven (28.9%) of 38 evaluable patients and 24 (75%) of 32 evaluable patients achieved RHF by 100 days and 1-year post-HCT, respectively. Discussion : Patients with HAL may successfully undergo AHCT with favorable outcomes. AHCT should be considered the standard of care for patients with relapsed/refractory HAL who meet standard eligibility criteria. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Rituximab In Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Chronic Lymphocytic Leukemia with Fludarabine + Total Body Irradiation Conditioning: Results of a Phase II Prospective Multicenter Study (ITAC 02-02)

Blood ◽

10.1182/blood.v116.21.3520.3520 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3520-3520

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Stephane Morisset ◽

Mohamad Mohty ◽

Gerard Socie ◽

...

Keyword(s):

Median Time ◽

Total Body Irradiation ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Lymphocytic Leukemia ◽

Positive Trend ◽

Hematopoietic Stem ◽

Total Body

Abstract Abstract 3520 Background: CLL remains incurable with standard therapies. Myeloablative allogeneic SCT (allo-HSCT) is still associated with high TRM and few late relapses. Recently, the major focus of transplantation in CLL has been with reduced-intensity conditioning (RIC) allo-HSCT, which is applicable to the more elderly patient population and which attempts to exploit the graft-versus-leukemia (GVL) effect that was proved in CLL Objective: To evaluate the efficacy and toxicity a RIC regimen including fludarabine and total body irradiation (TBI) with the introduction of rituximab for allo-HSCT in patients with a CLL stage B or C diagnosis. Materials and methods: This prospective study included adult CLL patients with age < 65 years in stage B or C in response after a salvage treatment either following at least 2 treatment lines (1 including fludarabine) or after a progressive disease after auto-HSCT, having a HLA identical sibling donor and a good performance status (Karnfosky >70%). Donors were mobilized by G-CSF and in case of collection failure, bone marrow aspiration was authorized. The conditioning included: rituximab 375mg/m2 on day -5, fludarabine 30 mg/m2 from day-4 to day-2, TBI 2grays (6-7 cGrays/minute) on day 0 and rituximab 500mg/m2 on day1 and day8. GVHD prophylaxis used cyclosporine A (IV 3mg/kg/day) from day-2 and mycomofetil fenolate oral (2g/day) from day 1. Results: Between April 2003 and December 2008, 40 patients were included, 34 (85%) males and 6 females with a median age of 54 years (35-65), 38 (95%) were in B stage at diagnosis and 2 in stage C. Among 23 explored for cytogenetics, 8 were abnormal (3 del17, 1 trisomy12, 1 t(8-11) & 1 del13). Before transplantation, 17 patients received 2 lines treatment, 10 three lines, 5 four lines, and 8>4. Only 1 patient received a previous auto-HSCT. Among 18 explored for Matutes status, 1 was in score 1, 1 in score 2, 3 in score 3, 5 in score 4 & 9 in score 5. At time of allograft, 7 (17%) patients were in complete response (CR), 29 (73%) in partial response (PR) and 4 (10%) < PR. For sex-matching, 59% were mismatched (27%of them were F>M). For ABO matching, 68% were compatible, 19% major incomp. & 13% minor incopm. The median interval diagnosis-allo-HSCT was 58 months (6-177). Median CD34+ number was 7.64 (3.1-18.7). Seven (17%) patients did not receive rituximab during conditioning because the protocol did not include it at the beginning and has been amended later. Thirty-nine (98%) patients engrafted with a median time to neutrophils recovery of 20 days (11-70), 79% of patients reached a total donor chimerism at day 90. Seventeen patients developed aGVHD grade ≥II (8 grII, 8 grIII & 1 grIV) with a cumulative incidence at 3 months of 44% (36-52). The cumulative incidence of cGVHD was, at 12 months: 29% (21-36) for limited and extensive; at 18 months: 32% (24-40) limited and 42% (34-50) extensive. After a median follow-up of 28 months (3-71), the median OS was not reached with 3 and 5-years probability of 55%(41-74). The median time of EFS was 30 months (15 - 70) with a 5-years probability of 46%(33-66). The cumulative incidence of relapse at 1 and 3 years was 17% (11-23) and 22% (15-29) respectively. The cumulative incidence TRM at 1 and 3 years was 10% (5-15) and 27% (20-35) respectively. At the last follow-up, 17 patients died, 6 due to relapse and 11 due to TRM. We noticed a high severe infection rate (56%) and 4% of deaths related only to infection. The univariate analysis showed a positive trend of rituximab on OS and relapse, and a significant protective effect on aGVHD>=2 (p=0.02). The multivariate analysis studying age, interval diagnosis-allo-HSCT, ABO and sex matching, disease status at allo-HSCT, CD34+ number, and rituximab, showed a positive significant impact of this last factor (rituximab) on OS and EFS [HR=0.1 [0-0.6] p=0.02 & HR=0.1[0-0.4] p=0.035 respectively]. Conclusion: We showed interesting results in terms of OS, relapse and TRM in patients with advanced CLL after Fludarabine/TBI allo-HSCT. The introduction of rituximab allowed a better outcome especially a significant reduction of incidence and severity of acute GVHD. Nevertheless there was still a high incidence of cGVHD, already known following the Fludarabine/TBI conditioning, leading us to propose either to increase the number of rituximab injections after allo-HSCT, or to test Fludarabine/busilvex/ATG associated to rituximab. Disclosures: No relevant conflicts of interest to declare.

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Single Institution Experience with Y-90 Ibritumomab Tiuxetan in the Treatment of Non-Hodgkin Lymphoma.

Blood ◽

10.1182/blood.v108.11.4699.4699 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4699-4699

Author(s):

Peter Martin ◽

Rene Michel ◽

Ahmed Galal

Keyword(s):

Hodgkin Lymphoma ◽

Median Time ◽

B Cell Lymphoma ◽

Similar Response ◽

Cell Transplant ◽

Single Institution ◽

Ibritumomab Tiuxetan ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Non Hodgkin Lymphoma

Abstract Background: Radioimmunotherapy (RIT) is an effective treatment of Non-Hodgkin Lymphoma (NHL). Nonetheless, the use of RIT outside of clinical trials has been limited. We report here the experience in 25 patients treated with Y-90 ibritumomab tiuxetan off-protocol at a single institution. Patients and Methods: The charts of all patients treated with RIT between October, 2004 and May, 2006 were retrospectively reviewed in accordance with Good Clinical Practice guidelines. 19 patients were treated with RIT alone while 6 were treated with RIT in combination with high-dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT). Dosimetry was not performed. Results: The median age of patients was 56 years (range 43–71 years). 13 of 25 had high-grade lymphoma (either transformed lymphoma or diffuse large B-cell lymphoma). The median IPI was 3. The median number of prior regimens was 3 (range 1–6). 6 patients had received fludarabine. 3 patients had undergone prior autologous HSCT and one had undergone allogeneic HSCT. The median time to platelet recovery >20 × 109/L was 35 days. One patient continues to have platelets <20 × 109/L 380 days post-RIT. The median time to recover platelets to >20 × 109/L was 72 among patients who had previously received fludarabine. Prior HSCT also appeared to be associated with prolonged thrombocytopenia. 7 patients remained neutropenic (ANC<0.5 × 109/L) for >30 days. One patient who had been treated with 4 lines of prior chemotherapy, including prolonged chlorambucil, developed acute myeloid leukemia at 6 months post-RIT. There have been 3 deaths to date, all due to disease progression at 1, 1, and 3 months post-RIT. The overall response rate in 21 of 25 patients was 84% with 9 patients achieving CR. With a median follow-up of 7 months, 5 patients have progressed. Conclusion: The use of off-protocol RIT in our institution was associated with similar response rates to those reported in patients treated on-protocol. Off concern, however, is the significant hematologic toxicity. There was an association between prior fludarabine and prolonged thrombocytopenia that has not been reported previously.

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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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Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽

10.1182/blood-2019-131332 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3714-3714

Author(s):

Lei Zhang ◽

Huacheng Luo ◽

Jing Li ◽

Hong-Min Ni ◽

Mark Sellin ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Low Dose ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Low Doses ◽

Hematopoietic Stem ◽

Increased Risk ◽

Leukemia Development ◽

Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

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CRP and ferritin in addition to the EASIX score predict CAR-T–related toxicity

Blood Advances ◽

10.1182/bloodadvances.2021004575 ◽

2021 ◽

Vol 5 (14) ◽

pp. 2799-2806

Author(s):

Uri Greenbaum ◽

Paolo Strati ◽

Rima M. Saliba ◽

Janet Torres ◽

Gabriela Rondon ◽

...

Keyword(s):

Cumulative Incidence ◽

B Cell Lymphoma ◽

Risk Groups ◽

Endothelial Activation ◽

Stress Index ◽

Cell Transplant ◽

T Cell Therapy ◽

Hematopoietic Stem ◽

Laboratory Parameters ◽

Car T

Abstract The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study’s objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T–related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.

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2694. Incidence of Pneumocytis jiroveci (PJP) Infection with 3-Month Prophylaxis of Aerosolized Pentamidine (AP) in Autologous Hematopoietic Stem Cell Transplantation (HSCT)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2371 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S947-S947

Author(s):

Sarah Perreault ◽

Dayna McManus ◽

Rebecca Pulk ◽

Jeffrey E Topal ◽

Francine Foss ◽

...

Keyword(s):

Cost Savings ◽

Cost Comparison ◽

High Dose ◽

Potential Cost ◽

Hematopoietic Stem ◽

Increased Risk ◽

One Year ◽

Relapsed Disease ◽

The Cost ◽

Autologous Hsct

Abstract Background HSCT patients are at an increased risk of developing PJP after transplant due to treatment induced immunosuppression. Given the risk of cytopenias with co-trimoxazole, AP is utilized as an alternative for PJP prophylaxis. A prior study revealed a 0% (0/19 patients) incidence when AP prophylaxis was given for one year post autologous HSCT. Current guidelines recommend a duration of 3 – 6 months for PJP prophylaxis in autologous HSCT. The primary endpoint of this study was to assess the incidence of PJP infection within one year post autologous HSCT in patients who received 3 months of AP. Secondary endpoint was a cost comparison of 3 months compared with 6 months of AP. Methods A single-center, retrospective study of adult autologous HSCT patients at Yale New Haven Hospital between February 2013 and December 2017 was performed. Patients were excluded if: <18 years of age, received < or >3 months of AP, changed to alternative PJP prophylactic agent or received no PJP prophylaxis, received tandem HSCT, deceased prior to one year post-transplant from a non PJP-related infection, HIV positive, or lost to follow-up. Pentamidine was given as a 300 mg inhalation monthly for 3 months starting Day +15 after autologous HSCT. Results A total of 288 patients were analyzed, no PJP infections occurred within one year post HSCT. Additionally, 187 (65%) patients received treatment post HSCT with 135/215 (63%) receiving maintenance immunomodulatory drugs for myeloma and 40/288 (14%) patients developing relapsed disease. 43% of the chemotherapy regimens for relapsed disease included high dose corticosteroids. The cost difference of using 3 months vs. 6 months of AP is $790, reflecting the cost of drug and its administration. Applying our incidence of 0%, potential cost savings of 3 months vs. 6 months of AP would be $330,000 over 5 years or $66,000 per year. Conclusion Three months of AP for PJP prophylaxis in autologous HSCT patients is safe and effective as well as cost-effective compared with a 6 month regimen. Disclosures All authors: No reported disclosures.

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Fludarabine Is Superior to Cladribine When Added to Busulfan and Low Dose TBI as Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT): A Prospective Randomized Trial.

Blood ◽

10.1182/blood.v104.11.1825.1825 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1825-1825

Author(s):

M. Markova ◽

Juliet N. Barker ◽

John E. Wagner ◽

Jeffrey S. Miller ◽

Mukta Arora ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Purine Analogues ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Reduced Intensity

Abstract Purine analogues have been combined with alkylator/irradiation as immunosuppressive and anti-tumor conditioning prior to allogeneic hematopoietic stem cell transplantation (HCT) though differing purine analogues have not been compared. We prospectively tested Fludarabine (F) 40 mg/m2/d x 5d vs. Cladribine (C) 10 mg/m2/d x 5d plus Busulfan (Bu) (2mg/kg q12h x 2d) and total body irradiation (T) 200cGy followed by cyclosporine and mycophenylate mofetil in 19 recipients of matched sibling peripheral blood stem cell and 13 unrelated donor (URD) marrow HCT. Patients in each randomly assigned cohort [FBuT vs. CbuT] were similar in age (median 52 years in both groups), diagnosis (leukemia/MDS 38 vs. 31%; lymphoid malignancy 57 vs 69%), extensive pre-HCT therapy (56 vs. 63%), high risk disease status (81 vs. 93%) and Karnofsky (median 90 in each)[all p= NS] though fewer FBuT were URD recipients 25% vs. CBuT 56%, p=0.07. Engraftment was prompt in both groups (median 11 vs. 12 days), but the cumulative incidence of neutrophil engraftment was 75% (95% C.I. 54–96%) using CBuT vs. 100% with FBuT (p<0.01) and randomization was halted. Platelet recovery was prompt (median FBuT 18 vs CBuT 24 days) and after FBuT 75% (95% C.I. 49–100) vs. CBuT 69% (43–95) recovered platelets > 50,000/μL by day +180, p=0.19. The cumulative incidence of GVHD after FBuT vs. CbuT was similar (acute grade II/IV 56 vs. 69%, p=0.26) and (chronic 50 vs. 31%, p=0.27). Transplant related mortality at day +180 was also similar [FBuT 25% (4–46) vs. CbuT 38% (14–61), p=0.47]. Survival was equivalent: at 1 year 50% in each group; at 3 years FBuT 25% vs. CBuT 38%, p=0.55. Multivariate analyses adjusted for age, donor type, diagnosis and stage as well as conditioning regimen showed lower relative risk (RR) of engraftment with CBuT (RR 0.6 (95% C.I. 0.2–1.3) p=0.16) and with URD RR 0.4 (0.2–1.0) p=0.04). RR of Platelet recovery was equivalent with FBuT (RR 0.7 (0.3–1.7) p=0.45) but inferior with URD (RR .16 (.05–.5) p<0.01). RR of GHVD II/IV similar with FBuT RR 1.1, p=0.95, but more frequent with URD RR 2.0, p=.2 and high risk status patients (RR 4.5, 1.5–13.5, =<0.01). Prevalence of remission (CR or PR) at 18 months was high and was similar in both groups (FBuT 100% vs CBuT 86%, p=NS). These data suggest that older patients with advanced hematologic malignancies can achieve satisfactory post-transplant outcomes using either of these combination/reduced intensity conditioning regimens. Fludarabine may be superior to cladribine as a component of pre-HCT conditioning with Bu/TBI due to reduced risks of graft failure. Further modifications of the regimen may confirm universal engraftment with even lower peri-transplant morbidity.

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Autologous Stem Cell Transplantation (ASCT) in HIV Associated Lymphoma (HIV-Ly) Patients: An Updated Analysis of the EBMT Lymphoma Working Party (EBMT-LWP) Experience.

Blood ◽

10.1182/blood.v110.11.1887.1887 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1887-1887 ◽

Cited By ~ 1

Author(s):

Pascual Balsalobre ◽

Jose L. Diez-Martin ◽

Alessandro Re ◽

Maria G. Michieli ◽

Josep-Maria Ribera ◽

...

Keyword(s):

Median Time ◽

Highly Active Antiretroviral Therapy ◽

Cumulative Incidence ◽

Bacterial Infections ◽

Conditioning Regimen ◽

Working Party ◽

Previous Treatment ◽

Median Number ◽

Viral Loads ◽

Highly Active

Abstract ASCT has been reported as a feasible, safe and effective treatment in HIV-Ly patients (pts) receiving Highly Active Antiretroviral Therapy (HAART). We hereby present an updated analysis of the EBMT experience on HIV-Ly pts treated with an ASCT since 1999. Sixty eight pts from 20 institutions [56 (82%) males, median age of 41 (29–62) years] were included. Twenty-two pts met AIDS criteria (other than lymphoma) at the time of HIV-Ly diagnosis. Forty-nine pts were diagnosed of NHL (31 DLBCL; 8 Burkitt/Burkitt-like; 4 plasmablastic; 3 anaplastic, 3 PTCL), 80% of them presenting with stage >II and 18 pts of HL, 61% of them presenting with stage >II. Median (range) lines of therapy before ASCT was 2 (1–5). Thirty-five pts were autografted in CR (16 in CR1), 25 in chemosensitive disease and 8 in chemoresistant disease. Sixty-five pts received the BEAM protocol as a conditioning regimen and the remaining three received TBI-based protocols. Two pts received more than 1 ASCT (censored at time of 2nd ASCT). At the time of ASCT the median number of CD4+ cells was 162 (8–1159)/mcl and 34 pts had undetectable HIV viral loads. HAART was given in 55/57 pts during conditioning but withdrawn in 25% of them. The median number of CD34+ cells infused was 4.5 (1.6–21.2) ×106/kg and G-CSF was used until engraftment in 60/67 pts for a median of 8 (2–21) days. All pts but one who died on day +15 reached neutrophils>500/ml at a median time of 11 (8–36) days. Platelet count >20.000/ml was reached in 61 pts at a median time of 14 (6–455) days. Twenty three pts (34%) died: disease-progression (n=15), acute ASCT-related complications (n=6) [bacterial infections (n=4), multi-organ failure (n=1), other complications (n=1)] and 2 pts died from HIV-related complications. Cumulative incidence of NRM was 4.4% (95%CI 1.5–13.3) and 7.6% (95%CI 3.3–17.6) at 3 and 12 months, respectively. Age > 50 years at ASCT [RR 4.37 (95%CI 1.01–18.89), p = 0.05] was the only independent adverse prognostic factor for NRM. Relapse occurred in 19 (28%) pts giving a cumulative incidence of 23.6% (15.2–36.9) and 29.6% (20.0–43.8) at 12 and 24 months, respectively. Median time to progression was 4.5 (0.5–32) months. Histology (NHL other than DLBCL) [RR 3.2 (95%CI 1.0–9.6), p = 0.04], the use of >2 previous treatment lines [RR 2.7 (95%CI 1.0–7.2), p = 0.05] and not being in CR at ASCT [RR 3.5 (95%CI 1.2–9.7), p = 0.02] were significantly associated with a higher risk of relapse post-ASCT. With a median follow up time of 32 (2–81) months, PFS and OS were 56% (CI95% 43–70) and 61% (CI95% 48–74) at 3 years, respectively. Pts with refractory disease showed a poorer OS [RR 5.1 (95%CI 1.8–14.6), p = 0.002] and PFS [RR 5.3 (95%CI 2.0–13.7), p = 0.001]. One pt developed an in-situ epithelioma and myelodisplastic syndrome (+4y) and another one a kidney adenocarcinoma (+3y). The results of the largest experience on ASCT for HIV-Ly indicate that this approach is a useful treatment in terms of NRM, long-term OS, and PFS, with significantly better results in patients autografted with chemosensitive disease.

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Phase II Prospective Multicenter Study of Treosulfan Based Reduced Intensity Conditioning In Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies From 10/10 HLA Identical Unrelated Donor

Blood ◽

10.1182/blood.v116.21.2353.2353 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2353-2353 ◽

Cited By ~ 1

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Stephane Morisset ◽

Nathalie Tedone ◽

Jacques-Olivier Bay ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Cumulative Incidence ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Grade Ii ◽

Reduced Intensity

Abstract Abstract 2353 Background: The key point in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to find the optimal balance between the graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect particularly in the unrelated HSCT settings, without forgetting the important role of conditioning. Objective: To evaluate the toxicity and efficacy of a new reduced intensity conditioning regimen including Treosulfan, followed by allo-HSCT from a 10/10 HLA identical unrelated donor. Materials and Methods: This prospective study included adult patients presenting a hematological malignancy in need of allo-HSCT using a 10/10 HLA identical unrelated donor. Accepted diagnoses were: CML in 1st chronic phase (CP) resistant to imatinib, in 2nd CP or in complete remission (CR) after blast crisis. Multiple myeloma (MM) or chronic lymphocytic leukemia (CLL) in stage B or C in response after relapse post-auto-HSCT. Acute lymphocytic or myeloid leukemia (ALL, AML) patients in CR1 at high risk or <CR1. Myelodysplasic syndrome (MDS) with poor prognostic factors. The conditioning included: Treosulfan 12g/m2/day intra-venous (day-6 to day-4), fludarabine 30mg/m2/day intra-venous (day-6 to day -2) and ATG 2.5 mg/kg/day (day-2 to day-1). GVHD prophylaxis used cyclosporine A oral (5mg/kg/day) or iv. (3mg/kg/day) from day-1. Peripheral stem cells after mobilization by G-CSF were used as HSC source. Results: Between February 2005 and July 2009, 56 patients were included in 5 different French centers, 30 (54%) males and 26 females with a median age of 57 years (18-65.5). There were 38 (68%) myeloproliferative disorders [29 AML (14 in CR1, 14 CR2 & 1<CR), 8 MDS (1CR1 and 7<CR) and 1 CML in CR1] and 18 (32%) lymphoprolifative disorders [9 MM in PR, 6 CLL (2CR1 & 4PR) and 3 ALL(1CR1 & 2CR2)]. Among 45 explored for cytogenetics, 23 (51%) were normal and 22 with poor prognostic. Before transplantation, two patients did not receive any previous treatment, 21 received 1 line, 22 two lines and 11 > 2 lines. For sex-matching, 49% of patients were sex-mismatched (half of them were F>M). For CMV, 43% were -/-, 25% +/+, 28% +/− and 1% -/+. For ABO matching, 52% were compatible, 24% major incomp. & 24% minor incopm. The median time between diagnosis and allograft was 15 months (4-168). The median number of infused CD34+ cells was 6.5 × 106/Kg(1-17.2) Fifty-four (96%) patients engrafted with a median time to neutrophils (>0.5G/l), and platelets (>50G/l) recovery of 16 days (4-86), 11 (4-82) respectively. Seventeen patients developed aGVHD grade ≥II (8 grade II, 2 grade III & 7 grade IV) with a cumulative incidence at 3 months of 31% (25-38). The cumulative incidence of cGVHD was, at 12 months: 32% (25-39) limited and 6% (2-10) extensive; at 18 months: 34% (27-47) limited and 8% (5-12) extensive. After a median follow-up of 13 months (1-57), the median overall survival (OS) was not reached with a 3 years probability of 52% (38-71). The median time of event free survival (EFS) was 15 months (8 - 57) with a 3-years probability of 47% (35-64). The cumulative incidence of relapse at 3 years was 25% (19-31) and the cumulative incidence of transplant-related mortality (TRM) at 12, 18 and 36 months was 20% (16-27), 23% (16-29) (same at 18 & 36 months) respectively. At the last follow-up, 22 patients died, 7 due to relapse and 15 due to TRM (5 pneumonia, 4 GVHD, 1 secondary malignancy and 6 other causes). We showed in a univariate analysis a higher 3-years OS of patients in CR1 (65%) compared to those <CR1 (44%) at transplantation with a significant better benefit for AML patients (76%). Patients with active cGVHD seem to benefit for the GVL effect on OS with a high significant difference (HR=0.2 (0.1-0.6) p=0.002). The multivariate analysis studying age, sex matching, ABO compatibility, CMV matching, type of disease, CD34+ cells number, cytogenetics, number of previous treatments, disease status and interval diagnosis-allo-HSCT showed: a negative significant impact of both minor ABO incompatibility (p<0.001) and CMV+/− (p=0.01) on OS, a negative significant impact of patients <CR (p=0.03) on relapse. There was no impact of studied factors on TRM. Conclusion: We showed very promising results in terms of OS, relapse and TRM with an impressive GVL effect, in heavily pre-treated patients and transplanted using unrelated donors. Treosulfan appears to be a good choice for conditioning especially with a better outcome in AML patients in CR1. Disclosures: No relevant conflicts of interest to declare.

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Cytogenetic Evolution (CE) In Patients (pts) with Low and Intermediate Risk Myelodysplastic Syndromes (MDS) Is Associated with Poor Prognosis

Blood ◽

10.1182/blood.v116.21.2941.2941 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2941-2941

Author(s):

Liunan Li ◽

Elias Jabbour ◽

Gautam Borthakur ◽

Stefan Faderl ◽

Tapan Kadia ◽

...

Keyword(s):

Disease Progression ◽

Cytogenetic Analysis ◽

Conflicts Of Interest ◽

Myelogenous Leukemia ◽

Intermediate Risk ◽

Hematopoietic Stem ◽

Increased Risk ◽

Significant Difference ◽

The Impact ◽

Cytogenetic Evolution

Abstract Abstract 2941 Introduction: MDS is a spectrum of abnormalities in the proliferation and differentiation of hematopoietic stem cells that result in peripheral cytopenias, bone marrow dysplasia and increased risk of transformation to acute myelogenous leukemia (AML). Cytogenetic abnormalities occur in more than 50% of patients (pts) and have an impact on survival and risk of transformation to AML. CE, or acquisition of additional clonal chromosomal abnormalities, has been reported to occur in 30 to 50% of primary MDS pts. Their impact on prognosis and transformation into AML among pts with low and intermediate risk MDS is not known. In this study, we analyzed the impact of CE on prognosis in lower risk MDS. Methods: we reviewed 722 pts clinic records of low and intermediate risk MDS pts at MD Anderson Cancer Center (MDACC) from 2000–2010 and conducted a retrospective analysis of all MDS pts with at least two consecutive cytogenetic analysis (365 patients, 50.6%) and compared the cytogenetic evolution group (CE group) with the group without cytogenetic changes (no CE group). Cytogenetic analysis was performed in the Cytogenetics Laboratory at MDACC. Results: CE was detected in 200 pts (55%). Characteristics of patients with CE are: median age 65 years (23-91), IPSS int-1 79%, diploid CG 42%, excess blasts 25%. Pts with CE were more frequently female (p=0.005), and had more frequently abnormalities of chromosome 5 and 7 (p<0.001) at baseline. There were no statistically significant difference between these two groups (p>0.05) regarding age, WBC, platelet, hgb, ANC, BM blasts percent, diagnosis (RA or RAEB), and IPSS score. There were more chr.-5/-7, insufficient metaphases, and other abnormalities, but less diploid cases in CE group compared with no CE group (p<0.001). History of malignancy (p=0.001) and prior chemotherapy exposure were also associated with CE (p=0.001), but this was not as strong for radiation exposure (p=0.066). Also, more CE patients required therapy for MDS compared to no CE patients (p=0.039). Progression free survival was significantly extended in no CE patients (p=0.02). Overall survival was a longer in no CE (34.1months), compared with CE group (26.2 months), although this was not statistically significant. Conclusion: CE is more commonly observed among pts with high-risk features, and is usually associated with disease progression and resistance. Also, prior malignancy and chemotherapy exposure were associated with CE in this study. This data indicates that genomic instability has a role in disease progression in MDS. Further analysis of CE in MDS is needed. Disclosures: No relevant conflicts of interest to declare.

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