GM-CSF in Stem Cell Transplant (SCT) Recipients: Impact of Graft-Versus Host Disease on Invasive Fungal Infections (IFIs)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4367-4367
Author(s):  
Amar Safdar ◽  
Gilhen Rodriguez ◽  
Georgina Georgescu ◽  
Richard Champlin
Keyword(s):  
Fungal Infections ◽  
Underlying Disease ◽  
P Value ◽  
High Dose ◽  
Cell Transplant ◽  
Retrospective Case ◽  
Graft Versus Host ◽  
Gm Csf ◽  
Younger Age ◽  
The Impact

Abstract Background: GM-CSF is thought to be beneficial in SCT patients with IFI. The impact of GM-CSF in SCT recipients with GVHD and IFI was evaluated Methods: A retrospective case-matched (GM-CSF [n = 12] vs. no GM-CSF [n = 27]) study was undertaken to compare outcomes if IFIs diagnosed >100 days following transplantation during 2000–2006. A response was defined as complete or partial response (CR/PR) and considered 3 months after IFI diagnosis or earlier in patients with earlier response. All value are given as median ± s.d. The systemic antifungal therapy in > 60% of patients included echinocandin and anti-mold triazole, or polyene agent. Results: Please refer to the table below. Patients who received GM-CSF were younger (age 36 ± 17 vs. 51 ± 13 years); neutropenic (<500 cells/uL) at onset of infection (50% vs. 11%; P = 0.014); had lower monocyte counts (10 ± 236 vs. 220 ± 575 cells/uL; P = 0.021) and frequently required intensive care unit stay (50% vs 15%; P = 0.043). A 50% response was observed in the GM-CSF treated SCT recipients with GVHD and IFIs, whereas, 41% response occurred in the group who received no concurrent Gm-CSF (P = 0.6). Similarly, IFI-associated deaths were less frequently observed in GM-CSF treated patients (41%) compared with 55% seen in patients who had not received GM-CSF (P = 0.7). There was a slight increase in survival among SCT recipients treated with GM-CSF (48 ± 21 days vs. 34 ± 19 days in no GM-CSF group P = 0.05) Conclusions: Late fungal infections in SCT recipients with GVHD, when treated with GM-CSF-based therapy had comparable outcomes despite having significantly more neutropenia, severe monocytopenia and ICU stay. Characteristics GM-CSF N = 12 (5% No GM-CSF N = 27 (%) p-value Underlying Disease-Leukemia Relapsed/refractory Cancer 10 (83) 5 (42) 18 (67) 6 (22) 0.12 0.26 Proven and probable IFI 9 (75) 21 (78) 1 GVHD (extensive) 5 (42) 14 (52) 0.57 High Dose Steroids 7 (58) 18 (67) 0.72 Disseminated IFI 3 (25) 4 (15) 0.65 Breakthrough IFI 10 (83) 25 (93) 0.57 APACHI II Score at time of IFI diagnosis 11+/−4 (range 5–18) 12+/−3 (range 5–19) 0.47

Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) in Stem Cell Transplant Recipients: Response to Immune Enhancement in Early Versus Late Serious Post-Transplant Infections

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4373-4373 ◽  
Author(s):  
Amar Safdar ◽  
Georgina Georgescu ◽  
Gilhen Rodriguez ◽  
Richard Champlin
Keyword(s):  
Cancer Recurrence ◽  
Apache Ii Score ◽  
High Dose ◽  
Cell Transplant ◽  
Post Transplant ◽  
Gm Csf ◽  
Transplant Patients ◽  
Invasive Infections ◽  
Concurrent Infections ◽  
The Impact

Abstract Background: The impact of GM-CSF therapy in SCT recipients with serious infection is not clear. We evaluated feasibility of GM-CSF therapy in transplant patients. Methods: Forty-seven patients with severe infections who had received 7 or more doses of GM-CSF between 2000 and 2006 were evaluated. Response was considered at the end of GM-CSF therapy in patients with complete or partial response (CR/PR). All values are given as median ± s.d. Serious infections were defined as systemic/invasive infections requiring hospitalization. Results: Age was 39 ± 18 years; 83% received allogeneic SCT, and 70% had leukemia. GVHD was noted in 36%; 60% of SCT recipients had cancer recurrence and 11% had graft failure. The APACHE II score was 15 ± 4. GM-CSF was given for 13 ± 12 (range, 7–57) doses. In only 1 of 5 patients with GM-CSF related adverse events (AEs), growth factor was discontinued due to persistent bone pain. Patients who received GM-CSF during late (>180 days) infections had higher CR/PR versus cytokine therapy for patients with early post-transplant infections (63% vs 35%, respectively; P = 0.06). Factors associated with treatment failure included: prior high-dose steroids (43% vs 4% in CP/PR; P = 0.01) multiple concurrent infections (65% vs 33% in CR/PR; P = 0.03), critical care unit stay (44% vs 5% in CR/PR; P = 0.001), mechanical ventilation (35% vs 4% in CR/PR; P = 0.01), serum bilirubin > 2mg/dL (30% vs 0%) in CR/PR; P = 0.004) and neutropenia (50% vs 17% in CR/PR: P = 0.02). Neutropenia was 25 ± 19 days in responders vs 34 ± 42 days in patients who failed treatment (P = 0.08). By logistic regression analysis, presence of multiple concurrent infections was associated with higher probability of death within 12 weeks of infection diagnosis (odds ratio, 4.76; 95% confidence interval, 1.1–20.5; P = 0.03). Conclusions: Treatment with GM-CSF was tolerated without serious AEs and may improve outcomes in patients with late post transplant infections.

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

scholarly journals Genetic and Non-Genetic Factors Association with Warfarin Long Term Therapy Stability in Sudan

2016 ◽  
Vol 8 (4) ◽  
pp. 100
Author(s):  
Azza A. M. H. Swar Aldahab ◽  
Abdallah. O. Elkhawad
Keyword(s):  
Vitamin K ◽  
Genetic Factors ◽  
Warfarin Therapy ◽  
Anticoagulation Therapy ◽  
Warfarin Dose ◽  
Term Therapy ◽  
P Value ◽  
Retrospective Case ◽  
The Impact

Anticoagulation with warfarin is characterized by a wide inter-individual variations in dose requirements and INR (International Normalised Ratio) stability, as there are evidences that warfarin response variability is associated with CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) and VKORC1 (Vitamin K epoxide reductase complex1) genetic polymorphisms. Carriers of CYP2C9*2 and VKORC11639G>A variant alleles are at greater risk of unstable anticoagulation therapy. Objectives: This retrospective case control study was directed to analyze the impact of genetic and non-genetic factors on warfarin therapy in Sudanese out-patients who were on long term warfarin therapy. Method: 118 Sudanese outpatients receiving warfarin treatment for at least six months, were interviewed for their non-genetic factors that included age, sex, indication for warfarin therapy, compliance, Vitamin K rich foods intake and concomitant drug therapy, in addition to their blood samples which were taken for DNA extraction and genotyping of CYP2C9*2 and VKORC11639G>A gene polymorphisms to study the genetic factors. INR stability % index was calculated, accordingly patients were classified into 2 groups, stable and unstable groups. Results: The frequencies of VKORC11639G>A alleles in Sudanese out-patients who were on long term warfarin therapy were 70.3% and 29.7% for the VKORC1/G and VKORC1/A alleles respectively. The frequencies of CYP2C9*2 alleles in Sudanese out-patients were 92.4% and 7.6% for CYP2C9*1 and CYP2C9*2 alleles respectively. Variables associated with low INR stability were VKCOR1/AA genotype (p-value = 0.028) and sex (p = 0.017). Variables that showed no association with INR stability were age (p-value = 0.259), compliance (p-value = 0.058). Vitamin K rich foods intake (p- value = 0.743), and mean stable warfarin dose (p-value = 0.439). Conclusion: Polymorphism in warfarin drug target gene VKORC1-11639G>A and sex are important elements of INR stability in Sudanese out- patients on long term warfarin therapy.

Naxitamab and GM-CSF for consolidation of high-risk neuroblastoma (HR-NB) patients in complete remission.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10021-10021
Author(s):  
Jaume Mora ◽  
Alicia Castañeda ◽  
Sara Perez-Jaume ◽  
Maite Gorostegui ◽  
Vicente Santa-María ◽  
...  
Keyword(s):  
Complete Remission ◽  
Fdg Pet ◽  
Treatment Initiation ◽  
Whole Body ◽  
Induction Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
Minor Response ◽  
Gm Csf ◽  
Spect Scan

10021 Background: Naxitamab was recently approved in the US in combination with GM-CSF for the treatment of patients (pts) with relapse/refractory HR-NB in the bone/bone marrow who have demonstrated a partial response (PR), minor response (MR), or stable disease (SD) to prior therapy. Here we describe the use of 5 cycles of naxitamab and GM-CSF through compassionate use for consolidation of HR-NB pts in first or subsequent complete remission (CR). Methods: HR-NB pts in CR (first or subsequent) after initial multimodal induction treatment were eligible. Disease status was assessed at study entry by histology of BM biopsies/aspirates obtained from bilateral posterior and bilateral anterior iliac crests, I-MIBG SPECT scan, and whole body MRI. FDG-PET was used for MIBG non-avid cases at diagnosis. Quantitative reverse transcription-polymerase chain reaction was used to assess MRD in pooled heparinized BM aspirates. Disease response was defined according to the revised INRC. Four BM aspirates and 123I-MIBG SPECT scan or FDG-PET scans were performed after cycles 2 and 5 and every 3 months thereafter for one year in all pts to assess response. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3.0 mg/kg/infusion (9.0 mg/kg/cycle) in combination with GM-CSF at 250 ug/m2/day on Days -4 to 0 and at 500 ug/m2/day on days 1 to 5. Treatment cycles were repeated every 4 weeks. Survival curves were built from the time of naxitamab treatment initiation by Kaplan-Meier methods and compared using the log-rank test. Results: From June 2017 to November 30 2020, 73 pts were treated: 55 (75%) in first CR and 18 (25%) in second or more CR. Majority of pts were MYCN non-amplified (n=56, 77%), all stage 4, median age at treatment initiation 4.5 years. 61 (84%) pts had received >5 cycles of induction chemotherapy; 22 (30%) high-dose chemotherapy and autologous stem cell transplant (ASCT); and 36 (49%) radiotherapy before receiving naxitamab. 58 (79.5%) pts completed naxitamab therapy, 53 (73%) in continued CR. 10 (14%) pts relapsed during treatment and 5 (7%) had grade 4 toxicities: 2 apnea related to naxitamab; and 2 non-related: 1 opioid related chest rigidity syndrome and 1 stroke. 3-y event-free-survival (EFS) for all pts is 58% [95% CI, 43.5; 78.4], 74% for first CR and 19% for second or more CR (p=0.0029). 3-y OS for the whole group is 82% [95% CI, 66.8; 100.0], 92% for first CR and 66% for second or more CR pts (p=0.18). Univariate Cox models for CR group, MYCN status, number of chemotherapies, ASCT, radiotherapy, MRD, and age showed significant p value only for prior relapse as predictor of EFS (p=0.047). Conclusions: Naxitamab for HR-NB pts in CR provided excellent 3-y OS rates regardless of previous management. The only predictor for relapse is prior history of recurrence.

A Complete Remission (CR) Is Not a Prerequisite for Prolonged Survival after Autotransplants for Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 926-926 ◽  
Author(s):  
Guido Tricot ◽  
Maureen Reiner ◽  
Jeffrey Sawyer ◽  
John Crowley ◽  
Bart Barlogie
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Tumor Burden ◽  
Time Dependent ◽  
Prolonged Survival ◽  
P Value ◽  
High Dose ◽  
Cytogenetic Abnormalities ◽  
Variate Analysis ◽  
The Impact

Abstract In acute leukemia prolonged survival is impossible without obtaining a CR. Based on the acute leukemia model, myeloma therapy has gradually been intensified with the aim to increase the CR rate as a first important step to improve overall survival (OS). Although patients with abnormal metaphase cytogenetics have a significantly inferior outcome in terms of event-free and overall survival, the CR rate is similar for patients with and without cytogenetic abnormalities, indicating that CR may not be a good prognostic indicator of ultimate outcome. To address the importance of obtaining a CR for OS, we analyzed our Total Therapy I (VADx3-high dose cyclophosphamide 6g/m2 with stem cell collection-EDAP-melphalan-based tandem transplants-α interferon maintenance) data in those patients who had not received any treatment prior to enrollment (N=155), received at least one transplant (N=135) and were alive one year after the first transplant (N=132). Kaplan-Meier curves were generated using a 1 year landmark to compensate for the guaranteed time of CR patients, but thereby excluding patients who died within the first year after the first autotransplant (N=3). The 1-year landmark was chosen because the large majority of CR patients (75%) had achieved their CR at 1 year after the first transplant. In addition, a time-dependent co-variate analysis for CR was performed, including the 135 patients. The median follow-up of these patients was 10.5 years. The 9 year OS after the landmark, i.e., 10 years after the first transplant, was 41% (95% confidence interval: 26, 55) for CR patients versus 37% (26, 47) for no CR patients (i.e., PR and <PR) with a logrank p value of 0.71 (Figure 1). Using a time-dependent co-variate analysis for CR, achieving a CR was not significantly related to OS (Hazard Ratio: 0.83; p value 0.39). Only the presence of metaphase cytogenetic abnormalities (HR: 2.0; p=0.005), LDH > 190 U/L (upper limit of normal) (HR: 2.0; p=0.01) and CRP >4.0mg/L (HR: 1.6; p=0.03) were significant for OS. When the importance of CR was assessed separately for patients with (N=43) and without (N=84) abnormal cytogenetic (cytogenetic information was missing on 5 patients), no survival benefit for CR patients was seen in either subgroup (p values 0.52 and 0.32, respectively) and similarly, using the time-dependent co-variate analysis for CR, there was no significant benefit for OS of attaining a CR in either group (p value: 0.7 and 0.5, respectively). We conclude that prolonged survival (>10 years) is observed in a substantial proportion of myeloma patients receiving a tandem autotransplant-based regimen, irrespective of the completeness of response to tandem transplants. The inherent genetic features of the myeloma and the impact on the micro-environment of the myeloma cells appear to be more important than the absolute tumor burden reduction accomplished by tandem transplants. Our findings may also be a reflection of the insensitivity of CR as an assessment of remaining tumor burden in myeloma and a new definition of CR may be required. Figure Figure

Phase II Window Study of the Farnesyltransferase Inhibitor R115777 (Zarnestra®) in Untreated Juvenile Myelomonocytic Leukemia (JMML): A Children’s Oncology Group Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2587-2587 ◽  
Author(s):  
Robert P. Castleberry ◽  
Mignon L. Loh ◽  
Nalini Jayaprakash ◽  
April Peterson ◽  
Vicky Casey ◽  
...  
Keyword(s):  
Phase Ii ◽  
Initial Dosage ◽  
Colony Growth ◽  
Juvenile Myelomonocytic Leukemia ◽  
Cell Transplant ◽  
Monocyte Count ◽  
Similar Frequency ◽  
Gm Csf ◽  
The Impact

Abstract JMML is a rare and often fatal leukemia of young children exhibiting unique clinical, hematopoietic and genetic features including GM-CSF hypersensitivity, and mutations of NF1, RAS, and PTPN11. Ras proteins control a number of cell signaling events becoming activated in part by the addition of a farnesyl moiety via farnesyl protein transferase (FTPase). Given that hyperactive Ras is central to JMML pathogenesis, it is intuitive that an FTPase is an appropriate therapeutic target in JMML. One FTPase inhibitor, L739,749, has previously been shown to abrogate spontaneous in vitro colony growth in 9 JMML samples (Blood 95:639, 2000). R115777 is a potent in vitro and in vivo inhibitor of FTPase, abrogating the growth of H-ras, K-ras and N-ras transformed tumors. In humans, it is well tolerated with the dose-limiting toxicities being myelosuppression and diarrhea. To assess the efficacy and toxicity of R115777 in JMML, a phase II window study was conducted as a part of COG study AAML0122 in newly diagnosed patients who were given the option of receiving this agent prior to cytosine arabinoside, fludarabine and 13-cis retinoic acid followed by stem cell transplant. R115777 was administered PO BID for 21 days with a 7 day rest for two courses in the absence of disease progression or excessive toxicity. The starting dosage in the first 11 patients was 200mg/m2 with escalation in subsequent patients to 300mg/m2 if the initial dosage was tolerated. Overall response was based upon changes in WBC and organomegaly. The impact of R115777 upon in vitro spontaneous colony growth, GM-CSF hypersensitivity and farnesylation was monitored. A total of 47 patients were accrued: M:F=30:17, median (med) age 15 mos. (1–76); med WBC 30X109/L (4–151); med monocyte count 18X109/L (1–55); med platelet count 58X109/L (2–587); elevated fetal hemoglobin 30 (65%). RAS and PTPN11 mutations were tested in 42 cases and inhibition of prenylation in 33. R115777 was well tolerated at both dosages with the most common grade 3/4 toxicities being thrombocytopenia (40%), anemia (40%), neutropenia (15%), and diarrhea (6%). There were no deaths during the trial. The table details the responses in patients receiving one course (N=47) and 2 courses (N=38) of R115777. The 9 patients not receiving two courses were removed from study due to lack of response or progressive disease. WBC ONLY 0VERALL (WBC & organomegaly) COURSE #1 CR CR PR MR SD PD Total     200mg/m2 6 0 4 4 2 1 11     300mg/m2 18 1 17 9 4 5 36 COURSE #2     200mg/m2 6 0 6 1 2 1 10     300mg/m2 17 2 14 7 2 3 28 FTPase activity was inhibited in 13/15 cases (med 71%; range 38–91%) with similar frequency and degree of inhibition at both dosages of R115777. There was no relationship between FTPase inhibition or response and the presence of RAS/PTPN11 mutations or inhibition of prenylation in an HJ2 assay. In conclusion, R115777 provides an overall CR/PR rate of 58% with no significant differences between the two dosages (p=0.7). This agent should be considered in the future management of JMML.

Treatment Intensification of Traditional BFM Therapy with 3 Chemotherapy Blocks and Double Delayed Intensification (Protocol II) Improves Outcome in Infants with High Risk (HR) Acute Lymphoblastic Leukemia (ALL): Results of Two Consecutive AIEOP Studies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Carmelo Rizzari ◽  
Maria Grazia Valsecchi ◽  
Paola De Lorenzo ◽  
Maurizio Aricò ◽  
Giuseppe Basso ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
P Value ◽  
High Dose ◽  
Treatment Intensification ◽  
Treatment Protocols ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Introduction: Cure rates of ALL in children aged less than one year (i.e. infants) at diagnosis are in the range of 35–40%. Encouraging results have been recently reported in infants by using intensified treatment, including high dose chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Aim: To evaluate the impact of the two treatment strategies adopted in the AIEOP ALL 91 and 95 studies on the outcome of ALL in infants. Patients and Methods: Fifty-two infants with ALL were enrolled between 1991 and 1999 in two consecutive studies, named AIEOP ALL 91 and ALL 95. Infants with an identified t(4;11) translocation had to be included in the high risk (HR) groups whilst those without this genetic abnormality could be treated in the intermediate (IR) or HR groups according to presenting features and treatment response. Patients belonging to the IR groups received a traditional BFM back-bone based treatment (protocols I, M and II), while those classified in the HR groups underwent an tensified treatment including induction (BFM protocol IA only, in study AIEOP ALL 91, and IA+IB in study ALL 95), consolidation with either 9 blocks of non-cross-resistant drugs (ALL 91) or 3 blocks followed by the 8-drug reinduction regimen - BFM protocol II - repeated twice (ALL 95). All patients were given a continuation phase (reinforced in HR patients of study ALL 95 by vincristine/prednisone pulses). Overall treatment duration was 2 years in both studies. Results: Infants in studies ALL 91 (n=21) and ALL 95 (n=31) had similar biological and clinical characteristics. The overall event-free survival (EFS) at 5 years was 45.0% (SE 7.0%). The EFS, after censoring for HSCT in 1st CR, was 38.1% (SE 11.4%) in ALL 91 and 51.6% (SE 9.9%) in ALL 95 (p-value=0.29). Patients treated in the IR arm of the two studies had a similar outcome. Better results were obtained in patients treated in the HR arm of ALL 95 study, where 9/17 chemotherapy-only patients and 3/4 HSCT patients are alive in CCR as compared to 1/7 and 0/2, respectively, in patients treated in the ALL 91 study. Discussion: These data show that full traditional BFM therapy intensified by 3 post-induction chemotherapy blocks and double protocol II (adopted in study ALL 95), is associated with a better outcome in infants with HR ALL.

Phase III Randomized Stem Cell Mobilization Trial Comparing Standard Vs Double-Dose G-CSF Vs Standard Doses of G-CSF Plus GM-CSF in Hard to Mobilize Patients Undergoing An Autologous Hematopoietic Stem Cell Transplant (HSCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3228-3228
Author(s):  
Elizabeth Berger ◽  
Christopher Seet ◽  
Mala Parthasarathy ◽  
Tulio Rodriguez ◽  
Scott E. Smith ◽  
...  
Keyword(s):  
Stem Cell ◽  
Standard Dose ◽  
Stem Cell Mobilization ◽  
Phase Iii ◽  
Control Group ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Cell Mobilization

Abstract Abstract 3228 Poster Board III-165 Introduction Using standard dose G-CSF (10 μg/kg) for stem cell mobilization, 25-40% of patients, deemed to be hard to mobilize based on prior therapy, will not collect sufficient HSC (> 2-2.5 × 106 CD34/kg) to proceed to a prompt autotransplant. Strategies to improve CD34/kg yields have included dose escalating G-CSF up to 30 μg/kg or combining G-CSF and GM-CSF. While dose escalated G-CSF is effective in increasing CD34 yields in normal donors as is the combination of G-CSF and GM-CSF, their comparative value in pre-treated patients has not been tested. To determine the value of these strategies, we performed a randomized comparison of high dose G-CSF (30 μg/kg as 2 doses 12 hours apart), to the combination of simultaneous single daily doses of G-CSF (10 μg/kg) plus GM-CSF (5 μg/kg), to a control group receiving G-CSF at an equivalent total dose of cytokine to the combination arm (15μg/kg) as a single dose. Patients and Methods Patients were eligible if heavily pre-treated, defined as: a minimum of 10 total cycles of combination chemotherapy and two prior regimens, or a total of 6 chemotherapy cycles if the patient also received RT to marrow bearing sites, platinum-based chemotherapy or 2 or more cycles of any BCNU or fludarabine containing regimen. Baseline WBC had to be > 3000/μl, ANC > 1500/μl and a platelets > 100,000/μl. Twelve liter aphereses began on day 5 of mobilization, and continued until ≥ 4 × 106 CD34/kg were collected or a maximum of 5 aphereses. Patients typically proceeded to transplant if they had ≥ 2.5 × 106 CD34/kg collected and were always re-mobilized if they collected < 2.0 × 106 CD34/kg. CD34 subsets (CD34+/CD33- and CD34+/CD38-) were also assessed for the 3 groups to determine if more primitive HSC were mobilized by the 2 novel strategies. The sample size was calculated based as follows: 60% of the control group would collect 2.5 × 106 CD34/kg and this would rise to 90% in one or both study arms. The detection of such differences with a power of 80% and a 2-sided alpha level of 0.025 required a total sample of 120 patients. Results A total of 120 patients were randomized; 119 were eligible. Patient demographics, shown in the Table, were matched among the three groups: The % of patients collecting ≥2.5 × 106 CD34/kg was: standard G: 60%, high dose G: 57% (p = 1.0), G + GM: 41% (p = 0.1). Median CD34 collected in first mobilization were, 3.6 × 106/kg, 3.0 × 106/kg (p = 0.22) and 2.0 × 106/kg (p = 0.05) respectively in a median of 4, 4, and 5 aphereses (p = NS). Re-mobilization rates: standard G; 37.5%, high dose G: 35%; G + GM: 50% (p = NS). Total median CD34 collected from first and any second mobilizations were: standard G: 4.8 × 106/kg, high dose G: 3.9 × 106/kg, and G + GM: 3.5 × 106/kg. One patient in the standard G arm and 3 in high dose G did not proceed to transplant due to poor initial mobilization and progression in 2, and one each for progression or poor mobilization alone. There were no significant differences in median engraftment times: for ANC, 10, 11 and 15 days respectively for the standard G-, high dose G- and G + GM arms and for platelets, 11, 13 and 14 days respectively. The overall survivals @ the median f/u time of 37 months were 59.8%, 61.8% and 48.1% respectively (p = 0.272) for the three groups. The % primitive HSC (CD34+/CD33- and CD34+/CD38-) from the first mobilization were identical in the 3 patient groups. Conclusions We found no advantage to dose escalated G-CSF nor to the combination of G-CSF and GM-CSF to mobilize HSC for autotransplantation in heavily pre-treated patients. We also did not find higher numbers of more primitive CD34 subsets mobilized by these newer strategies. Alternative approaches, e.g. the combination of plerixifor + standard dose G-CSF (Stiff et al: BBMT; 15:249-56, 2009) would appear to be the preferred method of initial HSC mobilization for heavily pre-treated patients. Disclosures Stiff: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Hematopoietic Cell Transplant Co-Morbidity Index (HCTCI) and Multiple Myeloma (MM) Survival After Autologous Hematopoietic Cell Transplantation (AHCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4217-4217
Author(s):  
Anuj Mahindra ◽  
Ayman A Saad ◽  
Mei-Jie Zhang ◽  
Xiaobo Zhong ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Risk Groups ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Co Morbidity ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4217 Background: AHCT improves survival (OS) in newly diagnosed MM patients (pts) in large randomized trials. These trials have limited eligibility to younger, healthier pts. Selection of older pts and those with co-morbid illness for AHCT is problematic. HCT-CI, originally developed as predictor of post-allogeneic transplant outcomes, maybe valuable in stratifying risk of transplant related mortality (TRM) risk and OS in the AHCT setting. We investigated the relative impact of HCT CI along with other patient and MM related variables on outcomes after AHCT in a large cohort of transplant recipients. Methods: Outcomes of 1156 MM pts receiving AHCT after high dose Melphalan (MEL) between 2007 and 2010 reported to the CIBMTR (Center for International Blood and Marrow Transplant Research) were analyzed. HCTCI scores and individual comorbidities were prospectively reported at time of AHCT. Median follow up of survivors was 26 month. The impact of HCTCI and other potential prognostic factors including Karnofsky performance status (KPS) on OS were studied in multivariate Cox regression models. Results: HCTCI score was 0, 1, 2, 3, >3 in 42%, 18%, 13%, 13% and 14% respectively. Most common co-morbidities included pulmonary, diabetes, obesity, psychiatric, cardiac, renal and prior solid tumor. Using consolidated HCTCI scores, patients were stratified initially into 3 risk groups – HCTCI 0 (42%) vs. HCTCI 1–2 (32%) vs. HCTCI >2 (26%). Males and Caucasians were more likely to have greater HCTCI score. Higher HCTCI was associated with lower KPS <90 (33% in HCTCI 0 cohort vs. 50% in HCTCI >2). HCTCI score >2 was associated with MEL dose reduction to 140 mg/m2 (22% vs. 10% in score 0 cohort). Cytogenetic risk and MM related factors were not correlated with HCTCI. TRM at 12 month was 2%, 2%, and 3% for 3 risk groups. With extremely few TRM events, multivariate analysis did not suggest an impact of HCTCI. OS was 95%, 92%, 92% at 1 year and 87%, 81%, 80% at 2 year, respectively. OS was inferior for HCTCI >2 cohort (RR of death 1.48, p=0.02) and HCTCI cohort 1–2 (RR 1.37, p=0.04) compared with HCTCI 0 cohort. There was no significant difference in OS between HCTCI >2 vs. HCTCI 1–2 (p=0.64). Therefore the latter 2 groups were combined as the HCTCI >0 cohort [N=667] and compared with HCTCI=0 [N=489] in multivariate models. HCTCI >0 predicted inferior OS (RR of death= 1.41, p=0.01). Other significant predictors of inferior survival were KPS <90 (RR of death 1.61, p<0.01), IgA subtype (RR 1.64, p<0.01), >1 pretransplant regimen (RR 1.47, p<0.01), resistant MM at AHCT (RR 1.78, p<0.01). Major cause of death in both groups was progressive MM. Conclusion: In clinical practice, higher HCTCI score was associated with MEL dose reduction. Mortality after AHCT is predominantly related to MM progression/relapse with low incidence of TRM. Higher HCTCI scores were independently associated with inferior OS. KPS remains an important tool for risk stratification. Disclosures: No relevant conflicts of interest to declare.

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