scholarly journals Haploidentical Natural Killer Cell Therapy As an Adjunct to Stem Cell Transplantation for Refractory Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3827-3827
Author(s):  
Uday Prakash Kulkarni ◽  
Arun Kumar Arunachalam ◽  
Hamenth Kumar Palani ◽  
Nithya Balasundaram ◽  
Arvind Venkatraman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Transplant ◽  
Free Survival ◽  
Cell Donor ◽  
Cell Dose ◽  
Refractory Acute Myeloid Leukemia ◽  
Refractory Aml

Abstract Refractory acute myeloid leukemia (AML), defined as failure of 2 cycles of induction therapy at diagnosis or of 1 cycle at relapse, represents a subgroup with poor clinical outcomes. In our transplant cohort, the 5-year overall survival in this subgroup was 16% (Ganapule at al. JGO 2017). Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Our in-vitro and animal model data suggest that exposure to arsenic trioxide (ATO) results in enhanced NK cytotoxicity (Alex AA et al. Front. Immunol 2018). Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (FLAG ± idarubicin or mitoxantrone + etoposide for 3 to 5 days) followed by 1-week rest and then a reduced-intensity transplant with fludarabine + melphalan conditioning while in peak cytopenia. From February 2019, we initiated a phase II single arm clinical trial (CTRI/2019/02/017505) enrolling patients with refractory AML planned for a stem cell transplant in peak cytopenia. Patients received CD56-positive cells from an HLA haploidentical related family donor (other than the stem cell donor, wherever feasible) following cytoreductive chemotherapy. The NK cell donor preference strategy included presence of KIR ligand mismatch, greater number of KIR B motifs (or the B score), lower donor age, and negative donor specific antibodies tested using flowcytometry crossmatch (Figure 1a). CD56-positive selection was done using CliniMACS prodigy system. This was followed by overnight incubation of the CD56 positive cells in autologous plasma with 2 micromolar ATO and 500 U/mL of interleukin-2. The CD56 positive cells were then infused to the patient 1-day after the completion of cytoreductive chemotherapy. This was followed by a reduced intensity stem cell transplant (Figure 1b). The primary outcome variable was 1-year relapse free survival. From February 2019, 14 patients with median age 28 years (IQR: 15.75-31.5) were enrolled in this trial. Six were females. Six had primary-refractory AML while 8 had relapsed-refractory AML. The cytoreductive chemotherapy was FLAG ± idarubicin (n=7), Mitoxantrone + Etoposide (n=6) and GCLAC (n=1). The median blast percentage on flowcytometry MRD testing prior to NK infusion was 15.9% (IQR: 9.1%-54.5%) (n=11). The median B score for the NK cell donors was 2 (IQR: 1-3). The median age of the NK cell donor was 43 years (IQR: 36-49.5). KIR ligand mismatch with the patient was noted in 2 donors. The median CD56-cell dose infused was 46.16 x 10 6/kg (IQR: 25.06-70.36) (Figure 1c). Pre-defined release criteria, including sterile cultures, and endotoxin negativity were met in all cases. There was no infusion related toxicity. The median blast percentage on flowcytometry MRD testing done following NK cell infusion was 11.9% (IQR: 4.9%-47.6%) (n=8). One patient withdrew consent after NK cell infusion and did not undergo transplant. For the remaining 13 patients, the stem cell donor was HLA matched (n=4), HLA 9/10 matched (n=1) or HLA haplomatched (n=8). The median CD34 cell dose infused was 10 x 10 6/kg (IQR:7.51-11.6). Five (38.5%) patients died of immediate post-transplant complications (sepsis (n=3) on days 1, 2 and 28, cerebral venous sinus thrombosis (n=1) on day 1 in a patient treated with hormonal contraceptives for menorrhagia, and veno-occlusive disease (n=1) on day 15 in a patient undergoing a second transplant) while 2 (15.4%) did not engraft (both subsequently died of infective complications following engraftment post-second transplant). Of the remaining 6 (46.2%) patients who engrafted and survived beyond 1 month of the transplant, the day 28 post-transplant MRD was negative for 5 patients while it was positive in 1 patient (0.13%). On follow up, 2 (15.4%) patients developed disease relapse (on days 54 and 218 respectively) and died. The remaining 4 (30.8%) patients are alive and relapse free at last follow up (mean follow up of surviving patients is 16 months). One patient received a CD34 cell boost on day 96 (cell dose - 8.55 x 10 6/kg) for poor graft function. For the entire cohort, the estimated 1-year event free survival is 28.8% ± 13.1%(Figure 1d). Whereas, acute GVHD was noted in 3 patients (50%; out of 6 evaluable patients) and chronic GVHD was noted in 3 patients (50%; out of the 6 evaluable patients). Thus, haploidentical NK cell therapy as an adjunct to transplant is safe and merits further evaluation in patients with AML. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

Tandem Autologous Stem Cell Transplantation in Chemorefractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4554-4554
Author(s):  
Catherine Garnett ◽  
Chrissy Giles ◽  
Osman Ahmed ◽  
Maialen Lasa ◽  
Holger W. Auner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Stem Cell Transplant ◽  
Progression Free Survival ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Free Survival

Abstract Abstract 4554 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response. We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation. At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2. Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2). Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease. Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant Disclosures: No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for Refractory Acute Myeloid Leukemia in Pediatric Patients: The UK Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4404-4404
Author(s):  
Patricia M O'Hare ◽  
Giovanna Lucchini ◽  
Michelle Cummins ◽  
Paul Veys ◽  
Mike Potter ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Refractory Disease ◽  
Free Survival ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract INTRODUCTION The prognosis for children with refractory acute myeloid leukemia (AML) treated with chemotherapy is dismal and data on the outcome after allogeneic haematopoietic stem cell transplant (SCT) are scanty with reported leukemia free survival (LFS) rates of 10-20%. Thus there is significant controversy about whether SCT is appropriate in such patients (pts). We performed a retrospective, national study to analyse outcomes and prognostic factors for children undergoing SCT for refractory AML in the UK. METHODS A retrospective analysis of all pts <18 years of age reported to the BSBMT registry who received their first allogeneic SCT between 2000-2012 for refractory AML (ie >5% blasts in the bone marrow (BM) or proven extramedullary disease (EM) was performed. Source data verification (SDV) was performed to ensure pts were indeed refractory. The primary end-point was 5 year LFS. Secondary end-points were Relapse Rate (RR), Treatment Related Mortality (TRM), Graft Versus Host Disease (GVHD) and Overall Survival (OS). The Kaplan Meyer method was used to estimate survival data and Fisher's exact and Mantel-Cox Log Rank tests were used to compare disease- transplant- and survival-related variables. RESULTS Following SDV, a total of 44 pts from 13 centres were included in the study. The median age at SCT was 11.5 yrs and the median number of prior lines of chemotherapy was 3. The median time from diagnosis to SCT was 197 days. 23 pts had primary refractory AML and 21 had relapsed refractory AML. 12 pts showed adverse risk cytogenetics, 26 standard risk and 6 favourable. EM disease was documented in 5 pts. 42 children had >5% myeloid blasts in the BM immediately prior to conditioning and refractory disease was confirmed by cytogenetics/molecular genetics in 23. 2 pts were in BM remission but had frank EM disease. 38 pts (86%) received myeloablative conditioning (14 TBI based) and 6 (14%) had reduced intensity conditioning (RIC). In vivo T cell depletion was used in 25 pts. 15 pts (35%) were transplanted from an HLA identical family donor, 15 from a matched unrelated donor and 14 (32%) a mismatched donor. BM was used as the stem cell source in 18 (41%), peripheral blood in 20 (46%) and cord blood in 6 cases (14%). Median follow up was 4 years 10 months. 5 pts never achieved engraftment and had disease progression. The remaining 39 pts engrafted at a median of 15 days post-SCT. 30 pts (68%) achieved a complete remission (CR) following SCT. TRM at 1 year was 18% (5 infections, 1 cardiac failure, 1 GVHD-related). Acute GVHD occurred in 23 pts and was severe (grade ≥III) in 8 (19%). The incidence of chronic GvHD was low (1 limited, 2 extensive). Relapse was the major cause of treatment failure and occurred in 17 pts (39%) at a median 2.3 months post SCT. At last follow-up, 18 pts remain alive and in continuous complete remission (CCR). In this cohort, the 5 year OS and LFS were both 43% (95%CI 31-61%) (Figure1). Outcomes in pts with primary refractory disease (9/23, 39% in CCR) and those with relapsed refractory AML (9/21, 43% in CCR) were equivalent. Outcome for pts with cytogenetic confirmation of refractory disease was not statistically different (7/23, 30% in CCR) from the overall group. Pts transplanted with ≤30% blasts in the BM had improved outcomes (5-year LFS 52% vs 27%, p= 0.05). Likewise, the development of aGVHD of any grade was associated with a significantly better LFS (5-year LFS 56% vs 30%, p= 0.05). Cytogenetics including monosomy 7 (n=7) and molecular risk classification did not translate into a significant prognostic factor for relapse. Since RIC was used in only 6 pts, the impact of the intensity of conditioning cannot be determined. CONCLUSIONS This is the largest series of outcomes for SCT for refractory paediatric AML reported to date. Our data indicate that for selected pts, particularly those with a lower disease burden, SCT offers a realistic chance of salvage in both primary refractory and relapsed refractory AML (5 year LFS 43%) with acceptable toxicity. The association of aGVHD with improved LFS suggest a possible role in engineering a graft-versus-leukemia effect in this patient group. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Autologous stem cell transplant for primary CNS lymphoma results in prolonged progression free and overall survival

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7623-7623
Author(s):  
P. B. Johnston ◽  
B. P. O’Neill ◽  
S. M. Ansell ◽  
D. J. Inwards ◽  
L. F. Porrata ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Primary Cns Lymphoma ◽  
Autologous Stem Cell Transplant ◽  
Cns Lymphoma ◽  
Cell Transplant ◽  
Free Survival ◽  
Additional Therapy

7623 Background: Survival for patient with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now report on outcomes of patients who have had at least 1 year follow up post ASCT. Methods: Between June, 2000 and September, 2004, 11 patients underwent ASCT for PCNSL. The medical records of consenting patients were abstracted for the following information. Median age at transplant was 47 years old (range 30–67). Median number of prior treatments 1 (range 1–3). Median time from diagnosis to transplant was 7.5 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0–3). Disease status at transplant: First CR 5 patients, later CR or PR 6 patients. Results: Eleven patients underwent ASCT for PCNSL and have a minimum of 1 year follow-up. All patients received BEAM conditioning. Median follow up was 28.3 months. Four patients have relapsed at a median of 200 days (range 40–523). Of the patients who relapsed, one has died of disease progression and the remaining three are alive after additional therapy. Median overall survival and progression free survival from transplant have not been reached. Two year overall and event free survival are 89% and 61%, respectively. Conclusions: Although limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2–3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline. No significant financial relationships to disclose.

Autologous stem cell transplantation versus no transplant in patients above 70 with multiple myeloma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20509-e20509
Author(s):  
Christopher Lemieux ◽  
Lori S. Muffly ◽  
David Joseph Iberri ◽  
Andrew Rezvani ◽  
Robert Lowsky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Progression Free Survival ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Free Survival ◽  
First Line Therapy ◽  
Included Patient

e20509 Background: We evaluated outcomes of patients with multiple myeloma (MM) ≥ 70 years who were seen for Autologous Stem Cell Transplant (ASCT) consult, based on whether they underwent transplant vs. non-transplant treatment. Methods: 138 patients with MM ≥ 70 years (median 71, range 70-78) were evaluated in the BMT clinic from 1/2010 to 11/2019 for a transplant consult. Results: Of the 138 patients, 53 proceeded to ASCT. ASCT was not pursued in 85 patients despite most (79%) being eligible for transplant. Reasons for deferring ASCT in eligible patients included patient preference (48%, n = 32) and physician preference (52%, n = 35). 68 patients were seen during first-line therapy, of which 29 underwent upfront transplant. The remainder were seen at second-line or beyond. There was no difference in baseline characteristics among the 113 patients with available follow-up (ASCT = 53, non-ASCT = 60), including median age (71 vs. 72 years, p = 0.4), high-risk cytogenetics (41% vs. 31%, p = 0.4), high-risk HCT-CI (32% vs. 20% p = 0.2), and ISS stage III (34% vs. 27%, p = 0.6). In the 53 patients who underwent transplant, conditioning melphalan dose was 200 mg/m2 (75%, n = 40) and 140 mg/m2 (25%, n = 13). Day 100 transplant related mortality was 0% (n = 0). Progression-free survival (PFS) and overall survival (OS) were compared in patients who were seen for consultation within 1 year of diagnosis (n = 80). With a median follow-up of 27 months, median PFS amongst patients ≥ 70 years undergoing ASCT (n = 39) was 47 months compared to 34 months in the non-ASCT (n = 41) group, p = 0.006. Median OS was not reached in either group. Estimated 5-years OS was 76% in the ASCT group and 82% in the non-ASCT group (p = 0.6). There was no difference in PFS of patients ≥ 70 undergoing ASCT compared to a cotemporaneous cohort of patients < 70 (n = 639) from our institution (47 vs. 57 months, p = 0.3). Conclusions: Selected patients ≥ 70 years with MM undergoing ASCT have better PFS compared to patients with similar characteristics who do not undergo ASCT. ASCT is safe in this older population and outcomes were similar compared to younger patients. [Table: see text]

Allogeneic Hematopoietic Stem Cell Transplantation as a Promising Treatment for Natural Killer-Cell Neoplasms.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3331-3331
Author(s):  
Naoko Murashige ◽  
Masahiro Kami ◽  
Yukiko Kishi ◽  
Sung-Won Kim ◽  
Masami Takeuchi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Stem Cell Source ◽  
Promising Treatment

Abstract The efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for NK-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. A hematopathologist reclassified the pathological diagnoses according to the WHO classification. Of 345 patients from 76 hospitals who underwent allo-HSCT for malignant lymphoma, 32 had NK-cell neoplasms: extranodal NK/T-cell lymphoma (n=27), blastic NK-cell lymphoma (n=3), and aggressive NK-cell leukemia (n=2). Fifteen were chemosensitive and 17 chemorefractory. Nine were in CR at the time of allo-HSCT. Twenty-five had matched related donors, 3 mismatched related, 2 matched unrelated, and 1 mismatched unrelated donors. Stem-cell source was bone marrow in 11 and mobilized peripheral blood in 21. Conditioning regimens were myeloablative (n=26) and non-myeloablative (n=6). Total body irradiation was given to 23 patients. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin and short-term methotrexate in 27 patients. Grade 2–4 acute GVHD and chronic GVHD developed in 13 and 9, respectively. Nine died of disease progression, 4 of infection, 2 of veno-occlusive disease, 2 of acute GVHD, 1 of interstitial pneumonitis, and 1 of thrombotic microangiopathy. Two-year progression-free and overall survivals were 33% and 38%, respectively (median follow-up, 32 months). All patients who did not relapse/progress within 10 months achieved progression-free survival during the follow-up. In multivariate analysis, stem cell source (BM vs. PB; relative risk 3.33) and acute GVHD (grade 2–4 vs. grade 0–1; relative risk 2.56) significantly affected progression-free survival. Allo-HSCT is a promising treatment for NK-cell neoplasms. Figure Figure

Bendamustine, Etoposide, Cytarabine and Melphalan (BeEAM) Followed By Autologous Stem Cell Transplantation Produce a 3-Year Progression-Free Survival Of 75% In Heavily Pre-Treated Hodgkin and Non-Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2134-2134
Author(s):  
Giuseppe Visani ◽  
Pietro Maria Stefani ◽  
Saveria Capria ◽  
Lara Malerba ◽  
Piero Galieni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Disease Type ◽  
Cell Transplant ◽  
Free Survival ◽  
End Point

Abstract Background We previously demonstrated (Visani et al, Blood 2011) the safety of a new conditioning regimen with bendamustine, etoposide, cytarabine, and melphalan (BeEAM) prior to autologous stem cell transplant (ASCT) in resistant/relapsed lymphoma patients (EUDRACTnumber2008-002736-15). Furthermore, this regimen showed significant anti-lymphoma activity (80% CR). At the time of publication (2011), disease type (NHL versus HL) and disease status at transplant (chemosensitive versus chemoresistant) were the only statistically significant variables influencing PFS (p=0.01; p=0.007). However, median follow-up for surviving patients was short (18 months), therefore, it was not possible to draw final conclusions on the efficacy. Aims We evaluated the efficacy of the BeEAM regimen in terms of disease-free (DFS) and overall survival (OS) after a median follow-up of 41 months. Methods Forty-three patients (median age 47 years, range 18-70) with resistant/relapsed NHL (28) or Hodgkin lymphoma (HL, 15) were consecutively enrolled in the study. Twenty-one patients had primary refractory disease, whereas 22 had relapsed disease, 5 of whom where in second or subsequent relapse, at the time of enrolment. The study was designed according to Fleming’s method. The primary objective of the study was to determine the 36-months event free survival rate. We fixed the lowest acceptable rate as 40% and the successful rate as 60%, with a significance level a=0.05 and a power 1-b =0.80. At the time of publication, the median follow-up was 18 months, and therefore it was not possible to establish if we had met the primary end-point of the study. Results we updated the follow-up at 41 months after transplant. Thirty-one out of 43 patients are still in CR (72%), as documented by both PET and CT scan. Two patients with HL were refractory and rapidly died, whereas 10/43 patients (23%) relapsed after a median time of 7.5 months (range:3-23) from transplant. Five patients died (3 NHL, 2 HL), whereas 5 patients are still alive after relapse. Median PFS and OS were still not reached. Conversely, 3-year PFS was 75%, allowing our study to met its primary end-point. Interestingly, disease type (HL versus NHL) at transplant is no longer influencing PFS (p=0.7), and still does not influence OS (p=0.1). On the other hand, disease status at transplant (chemosensitive vs chemoresistant) is still a strong predictor of both PFS and OS (p=0.03 and p=0.009, respectively). At present, one patient developed myelodisplasia after transplant. No other late effects were observed up to now. Conclusions The new BeEAM regimen met the primary end-point of the study and confirms its safety, after 41 months of follow-up. Interestingly, NHL and HL were not statistically different in terms of both PFS and OS at 41 months of observation. These data confirm the high efficacy of this regimen in heavily pretreated non-Hodgkin, as well as Hodgkin lymphoma. Acknowledgments supported in part by AIL Pesaro Onlus. Disclosures: Ocio: Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding.

Long-Term Outcomes in Patients with Acute Myelogenous Leukemia (AML) Following Allogeneic Stem Cell Transplantation (AlloSCT) for Relapse After Initial Autologous Bone Marrow Transplant (ASCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2299-2299
Author(s):  
Mary-Elizabeth Percival ◽  
Lloyd E. Damon ◽  
Thomas Martin ◽  
Lawrence Kaplan ◽  
Weiyun Ai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Response Status

Abstract Abstract 2299 Poster Board II-276 Introduction: Patients with low- and intermediate-risk AML have several options for consolidation therapy, including chemotherapy alone and ACST or AlloSCT. Since randomized studies comparing these approaches show no option to be clearly superior to the others, several centers focus on sequencing of therapies in terms of patient tolerance and toxicity. Since 1986 our preferred consolidation regimen at UCSF for these patients consists of high-dose chemotherapy with ASCT. Consequently, at the time of relapse, we are often presented with the need for a second transplant (usually AlloSCT), in the setting of prior ASCT. As there is a paucity of data describing the toxicity and efficacy of AlloSCT in this setting, we designed this study to evaluate these parameters. Patients and Methods: This is a retrospective-cohort, single-institution study of patients with AML treated at UCSF between 1986 and 2008 and who received a second transplant at the time of relapse. Patients were identified through our prospective database, and data were collected from electronic medical records and primary clinical charts when available. Dates of death were corroborated with the social security database. Statistical analysis was performed using STATA (v9). Censoring date for all analyses was July 31st, 2009. This study was approved by the UCSF institutional review board. Results: Thirty-one patients with AML were identified who underwent an AlloSCT in the setting of relapse following a prior ASCT, with a median follow up of 54 months. The median time from the first to the second transplant was 17 months (range: 6 – 48). The median age at the time of the AlloSCT was 43 years (range: 20 – 64). Response status at the time of transplant was: 17 patients (55%) in complete remission (CR), 12 patients (39%) with less than CR, and 2 patients (6%) with response status unknown. The transplant was myeloablative in 14 patients (45%), non-myeloablative in 13 patients (42%), and cord-blood-based in 4 patients (13%). The donor was unrelated in 17 patients (55%). There were 7 (18%) treatment-related deaths in the first 6 months and 10 (32%) treatment-related deaths overall (pulmonary toxicity: 4, graft-versus-host-disease: 3, and infection: 3). Twelve patients (39%) died due to progressive disease. The median overall survival was 7 months, with 48% and 31% of patients being alive at 12 and 24 months respectively. Remission status prior to transplant was the most significant predictor of survival; the median survival among complete responders vs. all others was 19 months vs. 3.5 months respectively (p=0.006). Following transplantation, the median relapse-free survival among responders was 38 months, with 31% of patients being relapse-free at last follow-up. The time between transplants, as well as age, sex, and intensity of conditioning regimen had no effect on overall and relapse-free survival in our cohort. However, peripheral stem cell transplant was associated with improved overall survival (compared to bone marrow, p=0.02), though this likely reflects different eras of supportive therapy. Conclusions: Our results suggest that AlloSCT is an effective approach for patients with AML with relapsed or refractory disease after a prior ASCT. In this cohort spanning 22 years, treatment-related mortality from AlloSCT was 32%, and 31% of responders remain free of relapse with long-term follow-up. Disclosures: No relevant conflicts of interest to declare.

Addition Of Clarithromycin To Lenalidomide and Dexamethasone (BiRd) Is Effective In Multiple Myeloma After Progression On Lenalidomide and Dexamethasone

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1960-1960 ◽  
Author(s):  
Nilanjan Ghosh ◽  
Noah Tucker ◽  
Marianna Zahurak ◽  
Jocelyn L. Wozney ◽  
Ivan M. Borrello ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Disease Progression ◽  
Stem Cell Transplant ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Free Survival ◽  
Prior Therapy ◽  
Median Progression Free Survival

Abstract Background The combination of clarithromycin (biaxin), lenalidomide and dexamethasone (BiRd) has been previously shown by Niesvizky, R., et al as a very effective regimen in newly diagnosed myeloma (MM) with an overall response rate of 90.3% and a very good partial response (VGPR) rate of 73.6%. Long term follow up has shown a median progression free survival of 49 months. In a case control comparison, Gay, F., et al showed that BiRd has superior outcomes compared to lenalidomide and dexamethasone (Rd). Clarithromycin appears to optimize the pharmacologic effect of glucocorticoids by increasing the area under the curve and the maximum concentration levels of certain corticosteroids. Clarithromycin has immunomodulatory properties, partially mediated by the suppression of interleukin-6 and other inflammatory cytokines and may also have direct antineoplastic effects. Although the efficacy of BiRd in the frontline treatment of MM is well established, the effect of BiRd in patients who are refractory to Rd is unknown. Methods As part of an IRB-approved study we performed a retrospective analysis on all patients with MM in whom clarithromycin was added to Rd at the time of progression on Rd between January 2007 and March 2013. High risk MM was defined as having any one of the following: del(13q) by cytogenetics or t(4;14), t(14;16), t(14;20), -17p ,+1q21 on FISH/cytogenetics. International Staging System (ISS) stage was based on beta2 microglobulin and albumin at diagnosis of symptomatic myeloma. These data were available for 18 patients (75%). The definitions of progression, stable disease and response were as per the International Myeloma Working Group criteria. Event time distributions for overall (OS) and progression-free survival (PFS) were estimated with the method of Kaplan and Meier, and compared using the log-rank statistic, or the Cox proportional hazards regression model. Factors associated with BiRd response were selected based on cross tabulations and logistic regression modeling. Results 24 patients with MM who had disease progression on Rd had clarithromycin added to their regimen at the time of progression on Rd. Median age was 61 years (range: 41-80 years), 10 (41.6%) female, 11 (45.8%) had high risk features on cytogenetics or FISH, 6 (25%) had a prior stem cell transplant. All patients had shown evidence of disease progression on Rd prior to addition of clarithromycin. Median duration on Rd immediately prior to addition of clarithromycin was 5.2 months (range: 1.6-37.8 months). The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. One patient developed dyspepsia, metallic taste, nausea and diarrhea. A second patient experienced grade 3 transaminitis. 10 patients, 41.6% (95% CI: 22.1, 63.4), achieved ≥PR. The clinical benefit rate (CR+VGPR+PR+MR) was 45.8% (95% CI: 25.6, 67.2). The median time to response was 4.4 months (range: 1-13.6 months) and the median duration of response was 17.3 months (range: 7.4-130.5 months). Median overall survival was 25 months with a median follow-up of 27.5 months. The median progression free survival (PFS) was 4 months. Age and prior therapy were significant risk factors for PFS. Patients over the age of 60 had a higher hazard of progression or death than patients under the age of 60 (HR 3.48 95% CI 1.09-11.09, p=0.04). The hazard of progression or death was increased by a factor of 1.59 for each additional prior therapy HR= 1.59 (95% CI: 1.19, 2.11), p=0.002. Patients initially responding to Rd (n=10) were more likely to respond to BiRd (n=6), 60% (95% CI: 26.2, 87.8) compared to patients that did not have an initial response to Rd (n=14) in whom the response to BiRD (n=4) was 28.6% (95% CI: 8.4, 58.1), OR=3.75, p=0.13. High risk genetics, prior stem cell transplant, and prior response to Rd did not correlate with PFS or response to BiRd, although the numbers are small. Conclusion Addition of clarithromycin to lenalidomide and dexamethasone (BiRd) can overcome resistance to lenalidomide and dexamethasone in a subset of patients and lead to clinical durable responses. This retrospective data may serve the basis for prospective evaluation of this effect. Disclosures: Off Label Use: Addition of clarithromycin to overcome resistance to lenalidomide and dexamethasone.

Analysis of Beam (Carmustine, Etoposide, Cytosine Arabinoside, Melphalan) Versus High Dose Melphalan (HDM) with Autologous Rescue in Multiple Myeloma(MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5227-5227 ◽  
Author(s):  
Karthikeyan A. Ramasamy ◽  
Ruth Branford ◽  
Radha Selvaratnam ◽  
Aloysius Y.L. Ho ◽  
Rafael Duarte ◽  
...  
Keyword(s):  
Stem Cell ◽  
Performance Status ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
High Dose ◽  
Cell Transplant ◽  
Free Survival ◽  
Significant Prolongation ◽  
Disease Free

Abstract Autologous stem cell transplantation is an established treatment that leads to prolongation in overall and disease free survival in MM. BEAM and M have been widely used as conditioning regimen for autologous stem cell transplant (ASCT) in patients with MM. At our centre MM patients with low creatinine clearance (Crcl) and a low performance status were offered Melphalan only as conditioning regime for ASCT. We report on our experience of HDM in comparison with standard BEAM. Records of 53 consecutive patients who had ASCT for myeloma at our centre between 2000 and 2003 were examined. Patients were staged as per Salmon and Durie (SD) criteria and EBMT response criteria were used for assessment post transplant .35 patients had BEAM conditioning (SD criteria 31-IIIA, 3-IA, 1-IIA) and 18(SD criteria 14- IIIA, 4-IIIB) had M.).Patients who received BEAM had a median age of 55 (range 38–66), median follow up of 19 months and those who received HDM had a median age of 60 (range 45 –69), follow up of 20.5 months. Stem cell source was peripheral blood (PBSC) in 50 patients, 1 Bone marrow (BM), and 2 BM and PBSC. HDM at a Dosage of 140 –200 mg/m2was administered in all HDM cases except for 1 patient who had 70mg/m2 because of Crcl of 17.4 ml/min. BEAM group had Carmustine 300mg/m2 (−6), Ara- C 800mg/m2 (−5 to −2), Etoposide 800mg/m2 (−5 to −2), M 140mg/m2 (−1). Patients in the M group had significantly lower haemoglobin and higher serum creatinine levels in comparison with the BEAM group. The 100-day treatment related mortality (TRM) was 5.5 % in HDM group, which was comparable to 2.2 % in the BEAM group. 9 out of 18 patients who had HDM relapsed and 9 out of 35 patients who had BEAM relapsed at follow up with Median relapse free survival (RFS) being 575 days in HDM group and has not achieved yet in BEAM group (p= .017). This data confirm that BEAM ASCT lead to significant prolongation of disease free survival with low TRM.Our data also suggest the effectiveness of HDM in patients who because of poor performance status and/or abnormal renal function may not tolerate BEAM ASCT

Nucleated Cell (NC) Dose of Autologous (Auto) Marrow Graft Is Not Predictive of Engraftment after Auto-Bone Marrow Transplant (auto-BMT) Following Failed Peripheral Blood Stem Cell (PBSC) Mobilization.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5454-5454
Author(s):  
Stephen A. Strickland ◽  
Heidi Chen ◽  
Carole Hunt ◽  
Wichai Chinratanalab ◽  
Brian Engelhardt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Median Time ◽  
Marrow Graft ◽  
Free Survival ◽  
Cell Dose ◽  
Pbsc Mobilization

Abstract BACKGROUND: Auto-PBSC transplant has replaced auto-BMT. 10–30% of patients (pts) fail to mobilize adequate PBSCs. Previous studies have shown a correlation between infusion of marrow NC doses >2×108/kg recipient body weight and improved marrow engraftment as well as improved disease free survival (DFS). HYPOTHESIS: NC dose in auto-BMT following failed PBSC mobilization is not predictive of marrow engraftment. METHODS: Consecutive pts undergoing high-dose chemotherapy (HDC) and auto-BMT after failed PBSC mobilization were evaluated in this retrospective study. NC dose, CD34+ cell dose, time to neutrophil (ANC) engraftment, time to platelet (Plt) engraftment, and survival were reviewed. Spearman’s correlation was computed. Overall survival (OS) and progression free survival (PFS) were evaluated using Kaplan-Meier plots. RESULTS: 22 pts failed to mobilize PBSC and underwent bone marrow harvest followed by HDC and auto-BMT from 2001 to 2006. 3 pts failed G-CSF and 19 failed cyclophosphamide and G-CSF mobilization. The median age at transplant was 56 yrs (range, 9–69). The diagnoses included Non-Hodgkin lymphoma (NHL;14,64%), Hodgkin lymphoma (4,18%), acute myeloid leukemia (AML;3,14%), and multiple myeloma (MM;1,4%). The median number of salvage regimens prior to attempted PBSC mobilization was 1 (range, 0–4). The median NC and CD34+ cell doses of the marrow stem cell product infused were 3.7×108/kg (range, 1.4–6.8) and 1.0×106/kg (range, 0.3–3.0), respectively. All pts achieved ANC engraftment with G-CSF support at a median time of 20.5 days (range, 13–43). Only 55% (12/22) of the pts achieved Plt engraftment with a median time of 46.5 days (range, 23–92). The NC cell and CD34+ cell dose did not differ significantly in patients with ANC engraftment (≤20 days or >20 days), Plt engraftment (≤45 days or >45 days) or number of salvage regimens (≤1 or >1). There was no correlation between NC dose and time to either ANC engraftment (rho=−0.05, P=0.8) or Plt engraftment (rho=0.6, P=0.9). CD34+ cell dose did not correlate with time to ANC engraftment (rho=−0.2, P=0.4) or Plt engraftment (rho=−0.2, P=0.4). Median follow up was 322 days (range, 53 to 1700). Median overall survival (OS) was 1140 days and median PFS was 509 days (95% CI, 368 to 649). OS and PFS were not impacted by the number of salvage regimens prior to transplant. Overall mortality (OM) was 36% (8/22). Causes of death were progressive disease (6/8,75%) and treatment related mortality (2/8,25%). 10/22 (45%) pts are alive without post-transplant relapse (PTR) at a median follow-up time of 276 (range, 53 to 649). 6 of these 10 pts continue to have Plt counts <100×109/L. CONCLUSIONS: NC or CD34+ cell doses of auto-marrow graft do not correlate with engraftment in pts undergoing HDC and auto-BMT after failed PBSC mobilization. Caution should be exercised in interpreting marrow cell doses in this population. These pts have a high OM and should be appropriately counselled.

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