Allogeneic Stem Cell Transplantation Group Research Articles

Analysis of Positive Results of 18F-FDG PET/CT Imaging after Hematopoietic Stem Cell Transplantation in Lymphoma.

The purpose of this study was to differentiate between false-positive and true-positive positron emission tomography (PET) results after hematopoietic stem cell transplantation (SCT) for lymphoma involvement by analyzing several clinical variables and specific imaging features. Patients with lymphoma who received SCT and underwent post-transplantation 18F-FDG PET/CT scans between January 2013 and April 2021 at our institution were included. Associations between PET positivity and related clinical information were assessed using t-tests and χ2 tests. The significance of variables differentiating benign lesions from malignant FDG-avid lesions was evaluated by logistic regression analysis. Survival probabilities were derived from Kaplan-Meier curves and compared using the log-rank test. A total of 185 patients (235 post-transplantation PET/CT scans) were enrolled in our present study. Compared with those with true-positive PET results, patients with false-positive PET results exhibited a better prognosis. For the autologous SCT group, false-positive cases were more commonly seen when FDG-avid foci appeared outside the sites of the original disease (p = 0.004), and the integrated CT imaging showed negative results (p = 0.000). In multivariate logistic regression analysis, integrated CT results were the only significant factor. For the allogeneic SCT group, false-positive cases were significantly more commonly seen when DS = 4 (p = 0.046), FDG-avid foci appeared outside the sites of the original disease (p = 0.022), and the integrated CT imaging showed negative results (p = 0.001). In a multivariate logistic regression analysis, whether FDG-avid foci were in the sites of the original disease and integrated CT results were both significant factors. False-positive FDG uptake in post-transplantation PET was not uncommon. Several variables could provide an important reference to differentiate false-positive from true-positive post-SCT PET results for lymphoma involvement. ChiCTR2300067355.

Safety of a Weekly Administration of 10 mg/kg of Liposomal Amphotericin B for Antifungal Prophylaxis in Allogeneic Stem-Cell Transplant and Acute Leukemia Patients.

BackgroundOptimal antifungal prophylaxis approach for patients undergoing chemotherapy, acute leukaemia (AL) or allogeneic stem cell transplant (ASCT) for haematological malignancies has yet to be identified in this high risk setting.Patient and MethodsAn open-label, pilot multicentre study - initiated at Henri Mondor and St-Louis Hospitals (10 patients), Paoli-Calmettes Institute being secondary involved (13 patients) - was conducted between February 2004 and June 2005 in adult patients receiving induction or consolidation chemotherapy for AL or a myeloablative conditioning regimen for ASCT. Patients were either treated for 4 weeks (AL) from the beginning of chemotherapy or 8 weeks (ASCT) from transplant. Treatment consisted of a 2 hour weekly infusion of 10mg/kg liposomal amphotericin B (LAB). Premedication was not allowed prior to day 1 study drug infusion. The primary endpoint was the incidence of reported adverse events occurring during the course of prophylaxis treatment.ResultsTwenty three patients (14 males and 9 females), mean age 44 years (range: 20 to 79) were treated in this interim analysis (8 ASCT and 15 AL). Safety was monitored with particular attention to infusion-related reactions (IRRs) and nephrotoxicity. In a total of 60 infusions, 5 IRRs (8.3%) occurred (flush, shock, thoracic pain, bone pain and dyspnoea). These were exclusively observed on day one in 5 patients (21%). Seven patients (30%) reached serum creatinine (SCr) ≥1.5 times their baseline values. In the AL group, no patient discontinued LAB or required dose reduction during the study. In the ASCT group, 4 patients discontinued after the first infusion, 3 for IRRs and one for SCr increase related to the study drug and other factors, including reactions to concomitant drugs. One additional ASCT patient had discontinued study drug following the third infusion for SCr increase. Mean duration of prophylaxis was 18 days (range: 10–28) in the AL patients and 14 days (range: 6–31) in the ASCT patients.ConclusionA weekly dose of 10 mg/kg appears to be very well tolerated during induction or consolidation therapy for AL. In the ASCT setting where multiple drugs are concomitantly administered, appropriate timing for the initiation of high dose LAB prophylaxis is yet to be determined in order to optimise the safety profile of this regimen.

Outcome of stem cell transplantation for Waldenström's macroglobulinemia: analysis of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) Lymphoma Working Group.

The role of stem cell transplantation (SCT) for patients with Waldenström's macroglobulinemia (WM) remains undetermined. Therefore, we retrospectively evaluated the outcome of autologous and allogeneic SCT for patients with WM using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-six patients receiving autologous and 31 receiving allogeneic SCT were analyzed. The allogeneic SCT group included more patients with advanced disease status at transplant and received more lines of chemotherapy. The cumulative incidences of non-relapse mortality (NRM) at 1 year were 30.0% (95% CI, 14.7-46.9%) in the allogeneic SCT and 0% in the autologous SCT group. The estimated 3-year overall (OS) and progression-free (PFS) survival rates were 84.5% (95% CI, 66.0-93.4%) and 70.8% (95% CI, 53.0-82.9%) in the autologous SCT group, and 52.2% (95% CI, 32.5-68.6%) and 45.0% (95% CI, 26.3-62.0%) in the allogeneic SCT group. No patients died after the first 2 years following allogeneic SCT. In univariate analyses, disease status at SCT was significantly associated with PFS in autologous SCT, and with OS and PFS in allogeneic SCT. These results suggest that both autologous and allogeneic SCT have each potential role in WM. Allogeneic SCT is more curative for WM, but is associated with high NRM.

PS1501 QUALITY OF LIFE IN PATIENTS UNDERGOING CHIMERIC ANTIGEN RECEPTOR (CAR) - T CELL THERAPY VS. AUTOLOGOUS AND ALLOGENEIC STEM CELL TRANSPLANT FOR HEMATOLOGIC MALIGNANCIES

Background: CAR (chimeric antigen receptor)-T cell therapy has shown promise in hematologic malignancies, with some rapid and durable responses. It is now even being directly compared in clinical trials to established forms of cellular therapy like stem cell transplant (SCT) for some hematological cancers. However, CAR-T cell therapy is associated with significant adverse events, including unique toxicities like cytokine release syndrome and CAR-T cell related encephalopathy syndrome, which can occur in up to a third of patients. Impact of CAR-T cell therapy on short-term and long-term quality of life (QOL) of patients is not known. Given the significant short-term adverse effects of CAR-T cell therapy, it is important to evaluate its impact on QOL of patients, in addition to efficacy. Aims: The overall goal of our study is to evaluate quality of life and symptom burden over time in patients receiving CAR-T cell therapy and compare them to that of prospective cohorts of patients undergoing autologous and allogeneic SCT for hematologic malignancies. Methods: QOL was prospectively evaluated in adult patients with hematologic malignancies undergoing CAR-T therapy vs. those undergoing autologous SCT and allogeneic SCT. QOL was assessed using FACT-G questionnaire at baseline, 2 weeks and monthly thereafter for six months. Preliminary data regarding total FACT-G score (range 0–108) and subdomains of functional well-being (FWB; range: 0–28), physical WB (PWB; range: 0–28) emotional WB (EWB; range: 0–24) & social WB (SWB; range: 0–28) are described. Median scores are reported and groups were compared using Wilcoxon Rank Sum/Kruskal Wallis test. Results: 45 patients were recruited to the study (CAR-T: 10; Autologous SCT: 22; Allogeneic SCT: 13) from July 2018 to January 2019. Follow up data at 2 weeks and 1 month were available for 23 and 15 patients, respectively (Table). Median age was similar across three groups (61.4 to 62.5 years, p = 0.9). There was no statistically significant difference in baseline total FACT-G QOL scores, though scores were overall lower in the allogeneic SCT group (CAR-T: 85, autologous SCT: 84 and allogeneic SCT: 68, p = 0.13). The baseline scores in the subdomains of EWB and FWB were numerically higher in the CAR-T group, followed by autologous SCT group and were lowest in allogeneic SCT group. At 2 weeks vs. baseline, overall QOL decreased by only 2 points in CAR-T group vs. 22 & 18 points in autologous & allogeneic SCT groups (p = 0.09). At 2 weeks, change in PWB vs. baseline was less pronounced in the CAR-T group compared with others, with a median decrease of 1 point in CAR-T group vs. 9 points in autologous SCT group and 13 points in allogeneic SCT group, respectively. (p = 0.03). At 1 month, overall QOL was 6 points lower than baseline in CAR-T group vs. 3 and 14 points lower in autologous and allogeneic SCT groups, respectively (p = 0.34). Importantly, PWB had at least returned to baseline in the CAR-T group with a median increase of 1 point from baseline in the CAR-T group compared with a decrease of 2 points in the autologous SCT group and of 4 points in the allogeneic SCT group, respectively (p = 0.73).Summary/Conclusion: Preliminary data show that patients undergoing CAR-T cell therapy do not experience a more significant dip in QOL compared with autologous and allogeneic SCT, with some indication of better PWB in the short-term. Accrual & follow-up are ongoing. Updated results, including 3-month follow up will be presented at the meeting.

Low Rate of Cervical Cancer Screening among Women with Hematologic Malignancies after Stem Cell Transplant

Annual cervical cancer screening with Papanicolaou (Pap) and human papillomavirus (HPV) testing after stem cell transplant (SCT) is recommended, but the uptake is unknown. We aimed to determine the prevalence and predictors of cervical cancer screening in patients with hematologic malignancies. We searched MarketScan Commercial Claims database for women who underwent allogeneic or autologous SCT. The primary outcome was cervical cancer screening, defined as procedures or abnormal results for HPV and/or Pap testing according administrative codes within 2 years after SCT. A multivariable logistic regression model was fitted with cancer type, SCT year, age, geographic area, insurance plan, comorbidity, and presence of graft-versus-host disease (GVHD).The study included 1484 patients; 1048 patients (70.6%) had autologous and 436 (29.4%) allogeneic SCT. Mean age was 52.5 years. Overall, 660 patients (44.5%) had screening within 2 years after SCT, 214 (49.1%) with allogeneic SCT and 446 (42.6%) with autologous SCT (P = .02). In the allogeneic SCT group, patients with GVHD had a lower rate of screening than patients without GVHD (42.5% versus 55.4%, P < .01), and GVHD was associated with lower odds of screening (odds ratio, .50; 95% confidence interval, .32 to .79). In the autologous SCT group, patients with comorbid medical conditions had a lower rate of screening than patients without comorbidity (36.0% versus 45.7%, P < .01). In both allogeneic and autologous SCT groups older patients had lower odds of screening. Cervical cancer screening rates after SCT are low, particularly in patients with GVHD, who are at significant risk of second malignancies. Future work is needed to develop strategies to increase uptake.

The Impact of Ponatinib Versus Allogeneic Stem Cell Transplant (SCT) on Outcomes in Patients with Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) with the T315I Mutation

The Impact of Ponatinib Versus Allogeneic Stem Cell Transplant (SCT) on Outcomes in Patients with Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) with the T315I Mutation

Comparison of Continuation of HMA Vs Allogeneic Stem Cell Transplant and Its Timing in Myelodysplastic Syndromes: Can It Wait? Results of a Retrospective Study

▪Background: Allogeneic stem cell transplant (ASCT) is a curative option for patients with higher risk myelodysplastic syndromes (MDS). Hypomethylating agents (HMA) have been shown to improve survival of patients with MDS and have an excellent toxicity profile. In eligible patients, HMA and ASCT are used as complementary strategies. The aim of this study is to compare outcome with HMA alone vs HMA+ASCT where ASCT is used as consolidation approach or as salvage therapy after HMA failure.Methods: We performed a retrospective analysis of 216 patients with high-risk MDS who received HMA treatment at our institution from between April 2004 and October 2012; after HMA therapy, 61 (28%) patients underwent ASCT: 25 (41%) of them received as a consolidation treatment and 36 (59%) as a salvage therapy. The remaining 155 patients continued on HMA therapy until relapse or progression and did not receive a further ASCT. We used SPSS v.20 for all statistical analysis. Categorical and continuous variables were compared by chi-square and Student’s t test, respectively, and survival analysis was conducted using Kaplan-Meier analysis with the log-rank test and Cox regression for multivariate models. We also implemented a landmark survival analysis that considered median time to transplant.Results: Median age was 65 (20-89), and patients were older in the group that did not receive ASCT (69 vs 58 years; p=0.000). WHO diagnoses were RA/RARS in 31 patients (15%), RCMD in 43 patients (19.9%), RAEB in 133 patients (62%), CMML in 23 patients (11%), and unclassifiable MDS in 18 patients (8.3%). IPSS risk was int-2 in 107 patients (50%) and high in 61 (28%), and the percentage of inttermediate-2/high-risk MDS was higher in the ASCT group (89% vs 73%; p=0.001). High-risk cytogenetics were found in 71% of patients (82% in ASCT vs 67% in HMA alone; p=0.02).Patients received a median of 6 (1-58) courses of HMA. Overall response rate (ORR) to HMA was 45% (n=97), with 38% (n=82) having complete response (CR), 2% (n=5) partial response, and 5% (n=10) hematologic improvement. There were no significant differences between response to HMA in the ASCT group when compared to the group that did not receive ASCT (ORR: 46% vs 43%, p=0.3; CR: 38% vs 37%, p= 0.5).When we further analyzed the 61 ASCT patients, 25 (41%) received it as a consolidation after achieving response and 36 (59%) as a salvage therapy after treatment failure. Response to ASCT was CR in 65% of patients, and 20% were not evaluable due to early mortality.Median overall survival (OS) for the whole series was 14 months (12-16), with 1- and 2-year OS rates of 57% and 24%, respectively. To adjust for early mortality after ASCT and to eliminate any bias, we performed a landmark analysis after a median time of 7 months after ASCT. Patients who received ASCT had better survival. This advantage was more evident among patients who received ASCT as salvage therapy, although there were no differences between both strategies, with respective median survivals of 14 months for consolidation ASCT and 23 months for salvage ASCT (p=0.29)Furthermore, no significant differences in survival were observed between patients who received HMA alone and those who received ASCT as a consolidation therapy (median survival of 14 and 16 months; p=0.498), although there was a tendency for a better OS after 2 years of follow up: the OS for HMA treatment and HMA+ASCT consolidation were 68% and 56% at 1 year, 25% and 31% at 2 years, and 10% and 31% at 3 years. The 1-year survival rates for patients who received HMA alone, HMA followed by ASCT as consolidation, and HMA followed by ASCT as salvage were 68%, 56%, and 78%, respectively, and the 2-year survival rates were 25%, 31%, and 42%, respectively. In a Cox regression model to analyze effects on OS, receiving an ASCT (median OS of 13 (7-19) vs 10 months (8-12); HR 0.62 [0.42 – 0.92], p=0.018) and hemoglobin levels at diagnosis (HR 0.829 [0.73 – 0.93], p=0.002) had a significant impact.Conclusions: ASCT is a feasible and curative strategy for patients with MDS, both as a consolidation or a salvage therapy, and thus it can be a good option after HMA failure. However, its benefits as a consolidation therapy after HMA treatment compared with continuation of HMA treatment are not clear owing to early mortality related to procedure, so ASCT should be carefully considered in patients responding to HMA. DisclosuresBorthakur:Tetralogic Pharmaceuticals: Research Funding. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Ravandi:Incyte Corporation: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Champlin:Otsuka: Research Funding. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Allogeneic but Not Autologous Stem Cell Transplant Attenuates the Negative Prognostic Impact Dictated By Pretransplant MRD Positivity

Multiparametric flow cytometry (MPFC) detection of minimal residual disease (MRD) represents a robust surrogate for the quality of complete remission (CR) and reliably predicts clinical outcome. In our experience, MRD detection provides prognostically relevant information when assessed at the post-consolidation time point. Ten years ago we demonstrated that the amount of MRD before autologous stem cell transplant (AuSCT) affected outcome. More recently, other authors have extended this observation to allogeneic stem cell transplant (ASCT) showing that pre-transplant MRD is a major determinant of prognosis regardless of graft-versus-leukemia (GVL) effect. The aim of our study was to evaluate, in an extended series of patients submitted to AuSCT or ASCT, the impact of a pre-transplantation MRD positive (MRDpos) or negative (MRDneg) status on overall survival (OS) and disease free survival (DFS). We analyzed 173 MRDpos and 53 MRDneg patients of whom 67 were submitted to AuSCT and 51 to ASCT. Eighty-two patients received no transplant because of age, poor performance status or insufficient stem cell harvest whereas 26, all in the MRDpos group, relapsed before transplant delivery. In the AuSCT group, before transplant, 32/67 (48%) were MRDneg and 35/67 (52%) MRDpos, with MRDneg group showing a superior OS (55% vs 20%, p=0.007). In the ASCT group, before transplant, 45/51 (88%) were MRDpos and 6/51 (12%) MRDneg. For 21 out of 51 (41%) sources of stem cells were matched unrelated donors (12) or haploidentical donors (9). In this subgroup, MRDpos and MRDneg patients shared a comparable 5-years OS (60% vs 56%, p=NS), with a 36% survival gain for those MRDpos who received ASCT as compared to AuSCT. Among MRDneg patients, no survival differences were demonstrated between those submitted to AuSCT or ASCT (55% vs 60%, p=NS). Such a lack of difference is likely due to the higher treatment related mortality (ASCT 3/6, 50% vs AuSCT 2/32, 6%, p=0.003) which counterbalanced the lower relapse rate in the ASCT group (ASCT 0/6, 0% vs AuSCT 11/32, 34%, p=NS). In conclusion, ASCT confers a significant survival advantage to MRDpos patients, attenuating the negative prognostic impact of pre-transplant MRD positivity. ASCT may expose MRDneg patients to an excess of toxicity suggesting that in these patients the allogeneic option should be postponed after a second remission. In MRDpos patients, AuSCT does not represent a valid therapeutic choice and ASCT, which should be timely delivered, also considering alternative sources of stem cells. DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) After Surviving 5 Years of Initial Therapy with Interferon Alpha (IFN), Imatinib (IMA) or Allogeneic Stem Cell Transplantation (ASCT)

Abstract 2001▪▪This icon denotes a clinically relevant abstract Introduction:IFN and ASCT were the most commonly used treatment modalities for CML before 2001. The introduction of IMA as the preferred treatment for CML changed the treatment paradigms for this disease. CML pts are now expected to live longer and responses are prolonged in most cases. However, long-term outcomes including late relapses, durability of response, side effects, and late development of new medical conditions are largely unknown. Methods:We performed a chart review of pts with CML in CP treated at our institution who have survived at least 5 yrs of their initial IFN or IMA therapy, or 5 yrs after ASCT, to analyze their long-term outcome, risk of late relapse, and emergence of late side effects or new medical health problems. Results:469 pts with CML CP treated at our institution between 1981 and 2006 survived at least 5 yrs on their initial CML treatment. One hundred twenty five pts are described in this analysis: 25 pts in the IFN group, 50 pts in the IMA group (400 mg/d), and 50 pts in the ASCT group. Pts received their initial treatment a median of 1 month (range, 0.3 to 11), 1 month (range, 0 to 7), and 13 months (range, 1 to 126) from diagnosis, respectively. Median time on initial therapy for the IFN and IMA groups was 6.4 yrs (range, 5–8.5) and 10.8 yrs (range, 5.1–11.5). Characteristics of the pts at time of diagnosis were as follows: hypertension (HTN) was present in 12%, 30% and 2% of the IFN, IMA, and ASCT pts, respectively; cardiac disease in 12%, 8% and 2%, respectively; thyroid disease (Thy) in 8%, 8% and 2%, respectively. Median number of medications (MEDS) per patient at baseline was 1 (range, 0–5), 1 (range, 0–13) and 0 (range, 0–4), respectively. Complete cytogenetic response (CCyR) was obtained in 76% (n=19), 96% (n=48) and 100% (n=50) of the pts, respectively. Time to best CyR was 17.1 months (mos) (range, 6–59.1), 7.2 mos (range, 2.4–64.2) in the IFN and IMA groups, respectively. Loss of cytogenetic response after 5 years occurred in 91% (n=21, 2 pts had no initial response, 2 pts remained in CCyR), 10% (n=5) and 6% (n=3), respectively. Twenty pts (80%) on the IFN cohort were switched to IMA at a median of 7.4 yrs (range, 5.3–13.3) after diagnosis (19 occurring between yrs 2000 and 2001). Of these 20 pts 75% (n=15) achieved MMR or better after a median of 4 yrs (range, 0.6–10.2) on IMA. New medical problems that developed at the 5 year mark were a follows: Thyroid problems in 8%, 0% and 10%, respectively, HTN in 0%, 2% and 14%, respectively; cardiac in 0%, 4% and 0%, respectively; and other in 44%, 22%and 58%, respectively. Median MEDS per patient at the 5 year mark was 2 (range, 0–7), 4 (range, 1–12) and 2 (range, 0–15), respectively. New medical problems that developed by last follow up were a follows: Thyroid problems in 4%, 6% and 0%, respectively; HTN in 4%, 18% and 10%, respectively, cardiac in 8%, 4% and 4%, respectively; osteoporosis in 0%, 0% and 6%, respectively, and other in 44%, 32% and 26%, respectively. Median Meds per patient at last follow up was 4 (range, 0–19), 6 (range, 1–16) and 2 (range, 0–25), respectively. Secondary malignancies occurred in 8%, 10% and 12% of patients, respectively. Pts continued to be on initial treatment in 16% (n=4), 94% (n=47) and 94% (n=47), respectively. At date of last follow up, late relapses (beyond 5 yrs of initial therapy) occurred in 72% (n=18), 8% (n=4) and 2% (n=1), respectively. At median follow up of 18, 11, and 14 yrs respectively, 76% (n=19), 92% (n=46) and 92% (n=46) are alive, 64% (n=16), 86% (n=43) and 90% (n=45) in CCyR. Conclusion:CP CML pts treated with IMA or SCT and surviving 5 yrs beyond initial treatment have low incidence of late relapses. New medical problems including heart disease and secondary malignancies may occur in some pts, but most pts are still alive. Pts with CML require prolonged medical care even in the setting of lasting remissions. Disclosures:Jabbour:BMS: Honoraria; Pfizer: Honoraria, Research Funding; novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Induction Therapy Followed by Allogeneic Stem Cell Transplant for MPN Blast Phase: Outcomes From Mayo Clinic in Arizona

Abstract 1749▪▪This icon denotes a clinically relevant abstract BACKGROUND:We have previously reported that transformation of a myeloproliferative neoplasm (MPN) to acute leukemia or blast phase (MPN-BP) is accompanied by a median survival of 2.6 months (range 0–24.2 months) (Mesa et. al. Blood 2005) despite treatment. Allogeneic stem cell transplantation (ASCT) offers a potential for cure. We reviewed 13 patients with MPN – BP who were candidates for ASCT, and 8 of those patients received ASCT after induction chemotherapy. METHODS:Retrospective analysis of individuals who had a clear antecedent myeloproliferative neoplasm (essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) (either primary (PMF) or post ET/PV)), transformed to MPN-BP, and were candidates for ASCT. Clinical characteristics at each phase of illness, therapy at each phase of illness, and outcome of ASCT were assessed. RESULTS:Patients (MPN details): Thirteen patients (8 male, 5 female, median age at diagnosis of MPN 42 years in those who underwent ASCT and 64 years in those who did not receive ASCT (combined median 53 years, range 26–70)) were identified who met the inclusion criteria, of whom 2 had ET, 4 PV, 2 Post-ET MF, 1 Post-PV MF and 4 PMF. Jak2-V617F mutation was present in 7 of 8 patients tested. Treatments used during the MPN phase included hydroxyurea in 9 (+ busulfan in 1 and + anagrelide in 1), and thalidomide/prednisone in 2 (two patients received no treatment prior to MPN-BP). Patients (MPN-BP details):Transformation of an MPN to blast phase (from diagnosis of MPN) occurred after a median of 11 years in those who underwent ASCT and 8 years in non-ASCT (range 3 months to 30 years). At the time of MPN-BP diagnosis, 9 patients had an abnormal karyotype, 3 with complex karyotypes, 3 with trisomy 8 (sole abnormality), 1 with del(7q), 1 with del(13q). Leukemic induction consisted of standard anthracycline/cytarabine combination therapy (+/− etoposide), except for one patient received a study medication voreloxin. One patient who did not receive ASCT had remission after induction, but later expired from relapse, two expired soon after leukemic transformation, and two were too ill to receive induction. In the ASCT group (N=8), 5 patients achieved complete remission (CR) of their leukemia/return to MPN chronic phase (one of the five patients required a second induction to achieve CR), while 3 patients were considered primary induction failures due to persistence of > 5% blasts in the blood (2) or marrow (1) at the time of pre-transplant response assessment. The median time from diagnosis of MPN-BP to ASCT was 128 days.ASCT Details and Outcomes: Patients (median age of 55 years at time of ASCT; range 44–73) underwent ASCT (all HLA identical, 3 matched unrelated donors, 5 matched sibling donors) with either reduced intensity conditioning (n=6) or fully myeloablative conditioning (n=2). After a median follow-up of 488 days (range 127 – 1206), 6 of 8 patients are alive and free of disease. MPN-BP recurred in two patients at day 69 and 77 post-transplant; both patients eventually died of progressive leukemia, one after a second transplant. Acute GVHD occurred in 3 patients (1 grade III, 2 grade II), and chronic GVHD in 4 (2 mild, 2 moderate). All five patients who achieved CR (marrow and PB blasts < 5%) after induction therapy remain in continuous CR, while 2 of the 3 patients with evidence of persistent leukemia relapsed and died of MPN-BP. No patient died of transplant-related causes and all patients engrafted promptly. CONCLUSION:Rapid induction followed by ASCT can offer a curative path for individuals with MPN-BP. Although limited by small numbers, our data suggest that leukemic clearance (marrow blast percentage < 5%) prior to ASCT is associated with improved outcome. Disclosures:Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Outcome of Patients with Refractory Acute Leukemia Treated with a Third Induction Chemotherapy Regimen

Abstract 4305 BackgroundTreatment options are limited for refractory acute leukemia (AL) patients. Few data are available on the potential utility vs futility of a third course of induction chemotherapy. We have reviewed the characteristics and outcome of 35 patients treated with a third intensive induction course for refractory AL at our institution and other centers affiliated to the Quebec Leukemia Cell Bank (BCLQ). Methods and patientsAdult AL patients who never achieved complete remission (CR) or who relapsed within 6 months after 2 consecutive induction courses and who received a third line intensive induction course between 2000 and 2010 were included in this study. Clinical, laboratory and treatment data were collected from hospital and/or BCLQ files. Outcomes were measured after the third induction course. Primary outcomes were achievement of CR/CRi, overall survival (OS) at 12 months and event-free survival (EFS), defined as the percentage of patients alive and leukemia free at 12 months. Secondary outcomes included median OS, median duration of remission for those obtaining CR and treatment related mortality (TRM) associated with the third induction course. OS was estimated using the Kaplan-Meier method and survival curves were compared using the Log-rank test. Alive patients were censored at their last follow-up. ResultsThirty five patients met the inclusion criteria. The median age was 43 years old (20–62). Thirty one patients (89%) were diagnosed with AML and 4 patients (11%) with ALL or acute leukemia of ambiguous lineage. The median white blood cell count at diagnosis was 23 × 109/L (0.7–223). For AML patients, cytogenetics was favourable in 1 patient (3%), intermediate in 17 (55%) and adverse in 13 (42%). None of the 6 patients with normal karyotype for whom molecular characterisation was performed had a favourable genotype defined as NPM1 mutated without FLT3-ITD mutation. The patient with favourable karyotype had a variant t(8;21)(q22;q22) translocation without KIT mutation. Eighteen patients (51%) were primarily refractory to prior therapy and 17 (49%) had relapsed within 6 months of CR. The third line induction regimen consisted of cyclophosphamide and etoposide in 11 patients (31%), high dose cytarabine-based regimen in 10 (29%), mitoxantrone and etoposide in 7 (20%), fludarabine, cytarabine and idarubicin in 5 (14%) and other regimen in 2(6%). Patients with sustained remission after their third induction course were followed for a minimum of 12 months except for one patient alive and leukemia free at 6 months. Patients who were not in sustained remission have all been followed until death or transition to palliative care.CR after the third induction course was achieved in 6 patients (17%). At 12 months, OS was 11% and EFS was 6%. After the third induction, median OS was 5 months and median duration of remission was 6 months. Among 20 patients treated in our institution, the third induction TRM was 15% and median duration of hospitalisation, excluding patients who died in aplasia, was 38 days (20–70). Median OS was higher in the intermediate than in the adverse cytogenetics group (8 vs 2 mo, p=0.0008, figure 1) and in patients who achieved CR after third induction vs no CR (12 vs 4 mo, p=0.03). There was no difference in median OS between primary refractory and relapsed patients (8 vs 4 months, p=0.52).Allogeneic stem cell transplantation (SCT) was performed in 10 patients (29%) of whom 4 (40%) were in CR before transplantation. The only two long term survivors were in the allogeneic SCT group. Their percentages of blasts at transplant were 3 and 69 %. ConclusionOnly two refractory patients are long term survivors and they share several features: non adverse cytogenetics, young age (20 and 23) and they underwent allogeneic SCT. Adverse cytogenetics impinges negatively on outcome, even in this highly refractory group of subjects.The prognosis of AL patients with persistent disease after 2 induction courses is extremely poor and represents a major unmet therapeutic need. Refractory patients with adverse cytogenetics were unsalvageable in this series. The best approach for patients not in CR after 2 inductions probably remains allogeneic SCT, when possible. We consider that in patients who cannot be offered an allogeneic SCT, administration of a third course of conventional chemotherapy is practically useless. These patients should be considered candidates for investigational treatments. Disclosures:Bergeron: Merck: Research Funding; Roche: Honoraria; Celgene: Research Funding. [Display omitted]

Comparison of the occurrence of mold infection among patients receiving chemotherapy for acute leukemia versus patients undergoing stem cell transplantation

Invasive mold infections (IMI) are an important cause of morbidity and mortality in patients with hematological malignancies. Cumulative incidence numbers vary greatly, probably because local circumstances influence the incidence of IMI. Therefore, comparison of different patient groups at risk should be performed at one hospital. We performed a single-center retrospective analysis examining both adult patients treated with chemotherapy for acute leukemia or MDS and patients undergoing allogeneic or autologous stem cell transplantation (SCT) between June 2007 and August 2009. IMI were classified according to the EORTC criteria. A total of 211 patients with 237 predefined risk episodes were analyzed. A total of 22 IMI were observed: three of them were classified as proven, 15 as probable, and four as possible. No IMI were observed in the autologous SCT group. The incidence of proven and probable IMI in the allogeneic SCT group was 7.2%, and in the chemotherapy group, 14.3%. Patients with IMI had a higher mortality risk. We demonstrate for the first time that patients receiving intensive chemotherapy for acute leukemia have the highest risk of developing IMI during their treatment compared to patients with allogeneic SCT.

Re-analysis of the Outcomes of Post-Remission Therapy for Acute Myeloid Leukemia with Core Binding Factor According to Years of Patient Enrolment

The purpose of this study was to re-evaluate post-remission therapy outcomes after first remission according to years of patient enrollment in patients with core binding factor acute myeloid leukaemia. We conducted a retrospective study on 138 patients aged less than 60 years diagnosed with core binding factor acute myeloid leukaemia between 1994 and 2006, comparing allogeneic stem cell transplantation and high-dose cytarabine chemotherapy as post-remission treatment options after the first remission. The 5-year probabilities of disease-free survival and overall survival were not different between allogeneic stem cell transplantation and high-dose cytarabine groups. However, 3-year probabilities of disease-free survival (86.7% vs. 67.0%) and overall survival (90.0% vs. 67.3%) showed a trend towards improvement in the allogeneic stem cell transplantation group compared with the high-dose cytarabine group in cohort after 2003 (2003-2006), whereas outcomes were not different in cohort before 2003 (1994-2002). Especially, 3-year probabilities of disease-free survival (95.2% vs. 59.3%, P = 0.008) and overall survival (95.2% vs. 59.6%, P = 0.032) of allogeneic stem cell transplantation group were significantly better than high-dose cytarabine group in cohort after 2003 of acute myeloid leukaemia patients with t(8;21). The relative risk of overall survival with allogeneic stem cell transplantation, compared with high-dose cytarabine chemotherapy, was significantly improved in the cohort after 2003 (0.33; 95% CI, 0.07-1.48) when compared with that before 2003 (1.92; 95% CI, 0.77-4.82). In multivariate analysis in cohort after 2003, allogeneic stem cell transplantation as post-remission therapy was associated with better disease-free survival. Allogeneic stem cell transplantation is currently the more effective post-remission therapy than it was prior to 2003 for core binding factor acute myeloid leukaemia achieving first remission. On the contrary to previous findings, allogeneic stem cell transplantation provides significantly improved outcomes than high-dose cytarabine chemotherapy in acute myeloid leukaemia with t(8;21).

Autologous or Allogeneic Stem Cell Transplantation in Patients with Waldenstrom’s Macroglobulinemia

The role of hematopoietic stem cell transplantation (SCT) in Waldenstrom’s macroglobulinemia (WM) has not been extensively studied. To determine the potential for long-term disease control using SCT in WM, we performed a retrospective review of 36 patients with WM who received autologous (n = 10) or allogeneic (n = 26) SCT and were reported to the Center for International Blood and Marrow Transplant Research between 1986 and 2002. The following outcomes were described: nonrelapse mortality (NRM), relapse, progression-free survival (PFS), and overall survival (OS). Median age at the time of SCT was 51 years (range, 30-76 years), and median time from initial treatment to SCT was 29 months (range, 2-198 months). A total of 78% of the patients had 2 or more previous chemotherapy regimens, and 52% had disease resistant to salvage chemotherapy. In the allogeneic SCT group, 58% of the patients received myeloablative conditioning regimens containing total body irradiation (TBI), and of the allograft recipients, 19% received nonmyeloablative/reduced-intensity conditioning. After a median follow-up of 65 months, 15 of the 36 patients (42%) are alive. Primary disease accounted for 29% of the deaths in the allogeneic SCT group and 25% of the deaths in the autologous SCT group. The relapse rate at 3 years was 29% (95% confidence interval [CI], 14%-48%) in the allogeneic group and 24% (95% CI, 4%-54%) in the autologous group. PFS at 3 years was 31% (95% CI, 14%-50%) in the allogeneic group and 65% (95% CI, 32%-91%) in the autologous group; OS was 46% (95% CI, 27%-65%) in the allogeneic group and 70% (95% CI, 40%-93%) in the autologous group. NRM at 3 years was 40% (95% CI, 23%-59%) in the allogeneic group and 11% (95% CI, 0-36%) in the autologous group. Autologous SCT is a safe and feasible treatment option for patients with WM, especially for those who present with adverse prognostic factors. Allogeneic SCT carries a much higher (40%) risk of NRM and should not be considered outside the context of a clinical trial.

Early Stem Cell Transplantation for Refractory Acute Leukemia after Salvage Therapy with High-Dose Etoposide and Cyclophosphamide

Primary refractory acute leukemia (AL) has a poor prognosis, although some patients can be salvaged with allogeneic stem cell transplantation (SCT). Induction of complete remission (CR) with conventional chemotherapy before SCT may improve outcome in this patient population. Between March 1991 and October 2003, 59 adults with primary refractory AL were treated with continuous-infusion etoposide (VP) 2.4 to 3.0 g/m 2 followed by cyclophosphamide (Cy) 6.0-7.2 g/m 2 intravenously over 3 to 4 days with the intention of proceeding to SCT in CR1. Forty-two patients had acute myelogenous leukemia (AML), 13 patients had acute lymphoblastic leukemia (ALL), and 4 patients had acute biphenotypic leukemia. The most frequent nonhematologic toxicities were oral mucosal, gastrointestinal, and hepatic toxicities (44%, 20%, and 15% of patients, respectively). Thirty-two (57%) of 56 evaluable patients entered CR1 with a median time to platelet and neutrophil recovery of 22 and 26 days, respectively. CR1 rates were similar in AML (54%) and ALL/acute biphenotypic leukemia (67%; P = .52), and analysis of baseline characteristics did not reveal any predictors of response to VP/Cy. Twenty-nine of 32 CR1 patients subsequently underwent SCT (24 allogeneic and 5 autologous). Estimated 5-year event-free survival (EFS) and overall survival for the entire cohort are 23% and 26%, respectively. In the allogeneic SCT group, 5-year EFS was 52% for AML patients and 14% for ALL patients ( P = .04), and only male sex was predictive of a favorable outcome ( P = .03). VP/Cy is able to induce CR1 in most patients with primary refractory AL with an acceptable toxicity profile. Subsequent allogeneic SCT can lead to long-term EFS in a significant proportion of patients.

Salvage of Primary Refractory Acute Leukemia (AL) with High-Dose Etoposide (VP) and Cyclophosphamide (CY) Followed by Early Stem Cell Transplantation (SCT): An Effective Treatment Strategy for AML but Not for All.

Primary refractory AL has a poor prognosis although some patients (pts) can be salvaged with allogeneic SCT. Induction of complete remission (CR1) with conventional chemotherapy prior to conditioning and SCT may improve long-term event-free survival (EFS). Between 03/91 and 10/03, 59 adults with primary refractory AL (defined as >15% marrow blast cells on day 30 of induction) were treated with VP 2.4 g/m2 by 34 hr. IV infusion beginning on day 1 followed by CY 2.0 g/m2 IV daily on days 3, 4 and 5 with hyperhydration (3 L/m2/d) as bladder prophylaxis. Six pts received VP 3.0 g/m2 and 1 patient received CY 1.8 g/m2 x 4 days. The study included 39 males and 20 females with a median age of 41 years (range 17–60). Diagnoses were AML (42 pts), ALL (13 pts) and biphenotypic AL (4 pts). Eleven pts (19%) presented with a WBC count > 50 x109/L and MRC karyotype was favourable in 4 pts, intermediate in 34 pts and adverse in 20 pts; metaphase analysis failed in 1 patient. All AML pts had already received high-dose cytosine arabinoside (HIDAC) and either daunorubicin (DNR) (n=33) or mitoxantrone and VP (n=9). ALL pts had previously received DNR, vincristine and prednisone with (n=9) or without (n=4) L-asparaginase. Biphenotypic AL pts had been induced with HIDAC, DNR, vincristine and prednisone. Induction day 30 marrow blast count was > 40% in 35 pts (59%). The most common grade I/II non-hematologic toxicities of VP/CY were oral mucosal (44% of pts), GI (20% of pts) and hepatic (15% of pts); only one patient developed grade III/IV toxicity (pulmonary). Median time to recovery of ANC > 0.5 x109/L and platelets > 20 x109/L was 26 and 22 days, respectively. Three pts (5%) died prior to day 21 of VP/CY and were not evaluable for response (2 pts sepsis, 1 patient pulmonary hemorrhage). Twenty-four pts (43%) were also refractory to VP/CY but 32 pts (57%) entered CR1. Response rates were similar in AML (54%) and ALL/ABL (67%) (p=0.52) and analysis of baseline patient characteristics did not reveal any predictors of response to VP/CY. Twenty-nine of 32 CR1 pts proceeded to SCT (24 allogeneic, 5 autologous); five pts with AL refractory to VP/CY also underwent allogeneic SCT although all subsequently relapsed. Four of the autologous SCT pts relapsed with only one patient remaining alive in CR1. Estimated 5-year EFS for the entire cohort of pts is 23%. The only positive predictor of survival was male sex (p=0.03) and cytogenetic risk group did not influence outcome (p=0.69). In the allogeneic SCT group, 5-year EFS was 45% and was signficantly better for pts with AML (52%) compared to pts with ALL (14%, p=0.04). In conclusion, VP/CY is able to induce CR1 in the majority of pts with primary refractory AL. For pts with AML in CR1 that have a suitable donor, subsequent allogeneic SCT results in a favourable long-term EFS. Although pts with primary refractory ALL have a high CR1 rate with VP/CY, overall outcome for this subgroup remains poor.

Autologous and Allogeneic Stem-Cell Transplantation As Salvage Treatment of Acute Promyelocytic Leukemia Initially Treated With All-Trans-Retinoic Acid: A Retrospective Analysis of the European Acute Promyelocytic Leukemia Group

To retrospectively determine the outcome of acute promyelocytic leukemia (APL) patients who underwent autologous or allogeneic stem-cell transplantation (SCT) during second complete remission. Of 122 relapsing patients included in two successive multicenter APL trials who achieved hematological second complete remission (generally after a salvage regimen of all-trans-retinoic acid [ATRA] combined with chemotherapy), 73 (60%) received allogeneic (n = 23) or autologous (n = 50) SCT. Seven-year relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) in the autologous SCT group were 79.4%, 60.6%, and 59.8%, respectively, with a transplant-related mortality (TRM) of 6%. Of the 28 and two patients autografted with negative and positive, respectively, reverse transcriptase-polymerase chain reaction before auto SCT, three (11%) and one relapsed, respectively. In the allogeneic SCT group, 7-year RFS, EFS, and OS were 92.3%, 52.2%, and 51.8%, respectively, with 39% TRM. OS was significantly better in the autologous SCT group than in the allogeneic SCT group (P = .04), whereas RFS and EFS did not differ significantly (P = .19 and P = .11, respectively). In patients not receiving transplantation, 7-year RFS, EFS, and OS were 38%, 30.4%, and 39.5%, respectively. These retrospective data suggest that autologous SCT is very effective in APL relapsing after treatment with ATRA if performed in molecular remission. Allogeneic SCT yields few relapses, but it is associated with high TRM when performed after salvage with very intensive chemotherapy. Salvage with arsenic trioxyde, which has lower toxicity, should further improve the outcome of relapsing APL, especially before allogeneic SCT.

Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and a review.

The most debilitating skeletal complication of stem cell transplantation (SCT) is avascular necrosis (AVN). Two hundred seven consecutive patients were evaluated prospectively for AVN. They survived disease free for more than 180 days after autologous or allogeneic SCT for hematologic malignancies. The diagnosis of AVN in suspicious cases was confirmed by magnetic resonance imaging. Possible correlations with treatments, bone mineral density (BMD), graft versus host disease (GVHD), and in vitro growth of fibroblast progenitors were investigated. Bone mineral density was evaluated by dual-energy X-ray absorptiometry in 100 transplanted patients, and the in vitro growth of fibroblast progenitors was monitored by a fibroblast colony-forming unit (CFU-F) assay in 30 patients after allogeneic SCT. Twelve patients developed AVN 3-114 months (median, 26 months) following SCT: 10 (10%) after allogeneic SCT and 2 (1.9%) after autologous SCT (P = 0.04). Twenty-five joints were affected by AVN. All patients had femoral head involvement, which was managed with hip replacement in six of them. All but one patient who developed AVN after allogeneic SCT suffered from chronic GVHD (cGVHD). Avascular necrosis occurred 1-4 months after exacerbation or progression of cGVHD. Cumulative dose of steroids was similar in both SCT groups (including steroids given pretransplant for the basic disease), whereas treatment duration was significantly longer in the allogeneic SCT group. Avascular necrosis was related to the decreased number of bone marrow CFU-F colonies in vitro, but not to BMD values. Avascular necrosis is a skeletal complication that occurs more often after allogeneic than after autologous SCT. Occurrence of AVN symptoms after clinical follow-up of cGVHD suggests that cGVHD requiring long-term steroid therapy is one of the main risk factors for AVN. Avascular necrosis may be facilitated by a severe deficit in the repopulating capacity of bone marrow stromal stem cells after SCT.