In patients with follicular lymphoma and a high tumor burden, the intergroup PRIMA phase III stud... more In patients with follicular lymphoma and a high tumor burden, the intergroup PRIMA phase III study was designed to evaluate the potential benefit of 2 years of rituximab (R) maintenance after response to first line R-chemotherapy induction regimens (patients registered from 12/2004 until 4/2007). At a median follow up of 3 years (Lancet 2011) and 6 years (Blood 2013 122:509), a significant sustained improvement in progression free survival (PFS) was demonstrated in patients receiving R-maintenance; hazard ratios (HR) of 0.55 and 0.58, respectively. We report here the long term results of this study with 4 additional years of follow-up. Patients initially randomized between observation (n=513) and R-maintenance (n=505) were all followed for 7 years after randomization and thereafter until the 31/12/16 after having given an informed consent for this extended follow-up period consisting of a yearly physician visit (imaging procedures were according to local center practices after year ...
Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source... more Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source of concern for specialists who also strive to preserve fertility. We studied whether gonadotropin-releasing hormone (GnRH) analogs could prevent the early onset of ovarian insufficiency postchemotherapy and protect fertility. The patients were divided into three groups: Control group 1 (Group A), premenarchal patients aged 3 to 7.5 years (n = 5), were not given GnRH analogs administered prior to PCT. Postmenarchal patients (Group B), aged 14.7 to 20 years (n = 12) with normal menstrual rhythm and ovulatory cycles, received treatment with GnRH analogs prior to PCT. Control group 2 (Group C), postmenarchal patients aged 15.9 to 20 years (n = 4), received PCT but no GnRH analog protection. All groups received the PCT regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT. In group B, leuprolide acetate inhibition was obtained with a depot injection administered each month before and during treatment with PCT. To accelerate the timing of ovarian regression, a subcutaneous injection (0.2 mg) was administered simultaneously. In Group A, patients had spontaneous menarche between the ages of 12 and 17.9 years, followed by normal menstruation and ovulatory cycles. Three patients became pregnant. After GnRH analog withdrawal, Group B patients continued with normal ovulatory cycles. Two patients became pregnant. Group C patients presented hypergonadotrophic hypoestrogenic amenorrhea. GnRH analog treatment before and during PCT enhances ovarian function and preserves adolescent fertility. The results must be confirmed in a larger study.
Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source... more Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source of concern for specialists who also strive to preserve fertility. We studied whether gonadotropin-releasing hormone (GnRH) analogs could prevent the early onset of ovarian insufficiency postchemotherapy and protect fertility. The patients were divided into three groups: Control group 1 (Group A), premenarchal patients aged 3 to 7.5 years (n = 5), were not given GnRH analogs administered prior to PCT. Postmenarchal patients (Group B), aged 14.7 to 20 years (n = 12) with normal menstrual rhythm and ovulatory cycles, received treatment with GnRH analogs prior to PCT. Control group 2 (Group C), postmenarchal patients aged 15.9 to 20 years (n = 4), received PCT but no GnRH analog protection. All groups received the PCT regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT. In group B, leuprolide acetate inhibition was obtained with a depot injection administered each month before and during treatment with PCT. To accelerate the timing of ovarian regression, a subcutaneous injection (0.2 mg) was administered simultaneously. In Group A, patients had spontaneous menarche between the ages of 12 and 17.9 years, followed by normal menstruation and ovulatory cycles. Three patients became pregnant. After GnRH analog withdrawal, Group B patients continued with normal ovulatory cycles. Two patients became pregnant. Group C patients presented hypergonadotrophic hypoestrogenic amenorrhea. GnRH analog treatment before and during PCT enhances ovarian function and preserves adolescent fertility. The results must be confirmed in a larger study.
Abstract 53 Prior studies have demonstrated a graft-versus-malignancy effect following allogeneic... more Abstract 53 Prior studies have demonstrated a graft-versus-malignancy effect following allogeneic HSCT that is variably linked to acute or chronic GVHD. Although a graft vs. Myeloma (MM) effect has been shown after myeloablative allogeneic HSCT, a higher treatment related mortality (TRM) risk leads to inferior survival compared with autologous HSCT. Non-myeloablative (NMA) and reduced intensity conditioning (RIC) approaches are used to reduce the risk of TRM while preserving the graft vs. MM effect. The clinical benefit of lower intensity conditioning regimens is thus especially dependent on the impact of acute or chronic GVHD on graft vs. MM effect and TRM. We analyzed the outcomes of 177 matched sibling allogeneic HSCT recipients reported to the CIBMTR between 1997 and 2005 following NMA (n=120) or RIC (n=57) performed within 18 months of diagnosis. Median age was 50 (range 24-69) years and 62% were Durie-Salmon Stage III. Tandem autologous followed by allogeneic HSCT (autologous+ allogeneic) recipients (n=105) were more likely to receive NMA conditioning vs. recipients of an upfront allogeneic HSCT (n=72). Majority (98%) received peripheral blood stem cell grafts. Outcomes at a median follow-up of 36 (3 - 98) months are summarized in table 1. In order to assess the impact of GVHD on outcomes, Cox proportional hazards regression models were built with GVHD as the main effect treating it as a time dependent covariate (Table 2). Other covariates in the multivariate models included age, sex, performance status, IgG vs. non IgG myeloma, disease status and chemosensitivity, prior lines of chemotherapy, donor-recipient sex match, NMA vs. RIC and year of transplant. AGVHD was associated with an increased risk of TRM. Tandem autologous + allogeneic HSCT was associated with reduced relapse risk (RR= 0.49, p=0.008). AGVHD had no impact on relapse/progression of MM while cGVHD was associated with a reduced risk of relapse (Figure. 1). The protective effect of cGVHD on relapse was significant in the non IgG MM subgroup. AGVHD had no impact on PFS whereas cGVHD was associated with superior PFS and lower risk of treatment failure. Later year of HSCT was also associated with superior PFS. Overall survival was not affected by cGVHD while recipients of tandem autologous + allogeneic HSCT had a higher mortality in the presence of aGVHD (RR=3.60, p= 0.01). After matched sibling allogeneic HSCT for MM, aGVHD is associated with a higher risk of TRM whereas cGVHD decreases the risk of relapse and improves PFS. The effect of cGVHD may vary with the type of MM with greater impact in non IgG MM. Further study to identify subtypes of MM susceptible to an immune mediated graft vs. MM effect is suggested. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.
Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transp... more Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (auto HCT). However, little information is available regarding the outcome of patients (pts) with the rarer immunoglobulin subtypes IgD and IgM, which represent 2% and 0.5%, respectively, of all MM cases. In addition, IgD MM has been reported previously to have a poorer prognosis, at least after conventional therapy. The CIBMTR conducted a retrospective analysis of MM pts transplanted between 1995–2005 to describe the characteristics and results of auto HCT in IgD (n=36) and IgM (n=11) among 3578 MM patients with auto HCT during this period. Median follow-up of survivors was 41 (range 2–130) months for pts with IgD and 58 (range 5–101) months for those with IgM MM. Among pts with IgD subtype, median age was 52 years (yrs), 67% were male, 36% had a creatinine >2 mg/L, 61% had Durie-Salmon stage III disease at diagnosis and 33% had Kappa Serum Light chain; the corresponding values for IgM pts were 58 yrs, 36%, 73% and 55% respectively. Prior to auto HCT, 75% of IgD pts were chemosensitive and 25% had received >2 lines of chemotherapy, while all IgM pts were chemosensitive and none had received more than 2 lines of prior therapy. Median time from diagnosis to auto HCT was 9 months in both subtypes. The most common conditioning regimen was singleagent melphalan, and all but 1 pt with IgD disease were grafted with blood stem cells. The small sample size precluded multivariate analysis for potential prognostic factors for outcome. Below table summarizes the post-auto HCT results in these pts contrasted with a reference pool of IgG and IgA MM receiving auto HCT in the same time period. Outcomes, probability (95% CI) IgD IgM IgG/IgA (n=36) (n=11) (n=1475) 100-day mortality, % 0 9 ( 0 – 32) 7 (5 – 8) Non MM deaths, % @ 1 yr 0 9 (0 – 32) 5 (4 – 7) @ 3 yrs 3 (0 – 13) 21 (2 – 51) 16 (14 – 18) Relapse/ Progression, % @ 1 yr 21 (9 – 37) 20 (2 – 49) 18 (16 – 20) @ 3 yrs 59 (41 – 76) 32 (8 – 64) 36 (34 – 39) Progression-free survival, % @ 1 yr 79 (63 – 91) 71 (41 – 93) 77 (74 – 79) @ 3 yrs 38 (21 – 56) 47 (17 – 78) 47 (44 – 50) Overall survival, % @ 1 yr 87 (74 – 97) 91 (68 – 100) 79 (77 – 85) @ 3 yrs 69 (51 – 84) 68 (36 – 93) 53 (50 – 57) No striking differences are apparent in the post auto HCT outcomes of patients with IgD and IgM MM. These results are also consistent with published outcomes of pts with IgD/ IgM MM (Wechaleker et al Ann Hematol. 2005 Feb; 84(2):115–7; Maisner et al Bone Marrow Transplant. 2008 Jan; 41(1):51–4).
Abstract 1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an over... more Abstract 1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an overall survival at 5 years of 80%. ABVD can be considered as gold standard for first line treatment for all stages of HL. Dividing patients (pts.) in different prognostic groups has aimed to reduce chemo and radio toxicity in those patients with good prognosis. A negative PET-CT, either early during treatment of ABVD or after completion of it, has shown to be a powerful prognostic tool (Hutchings: Blood 2006; Gallamini: Haematologica 2006). Our cooperative group has an experience with 584 patients with HL in early or advanced stage treated with 3 or 6 cycles of ABVD plus involved field radiotherapy with a complete remission (CR) of 91% and an event free survival (EFS) and overall survival (OS) at 60 months of 79% and 95%.(S Pavlovsky, Clin Lymp My & Leuk, 2010). Aims: Test the efficacy of treatment to all stages of HL adjusted to PET-CT results after 3 cycles of ABVD. Evaluate the outcome of pts. who have a negative PET-CT after 3 cycles of ABVD and receive no further treatment. Intensify therapy only in pts. who have persistent hyper metabolic lesions in PET-CT after 3 cycles of ABVD. Method: Since October 2005, 198 newly diagnosed pts. with HL have been included in a prospective multicenter trial. Initially all patients received 3 cycles of ABVD. After the third cycle, pts. were evaluated with a PET-CT. Those pts. who achieved CR with a negative PET-CT, received no further treatment. Those with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions by PET-TC after 3 ABVD were considered in partial remission (PR) and completed 6 cycles of ABVD and radiotherapy (RT) on PET-CT positive areas. Those patients with less than PR after 3 cycles of ABVD received ESHAP and if CR, high doses of chemotherapy and an autologous stem cell transplant (ASCT). All patients were re-evaluated at the end of treatment. The median follow up is of 30 months (3-62). Results: One hundred and seventy three patients completed three cycles of ABVD followed by a PET-CT. The median age at diagnosis was 29 years. One hundred and thirty-six (79%) had localized stage (I-II) at diagnosis and 37 (21%) presented with advanced stage (III-IV). Of 155 pts. 77 (50%) pts had IPS 0–1, 66 (43%) had IPS 2–3 and 12 (8%) had IPS 4–5. Twenty six (17%) pts. had bulky disease at diagnosis. One hundred and thirty-seven (79%) pts. achieved CR with negative PET-CT after 3 cycles of ABVD. Thirty-six (21%) were PET-CT positive, of them 32 pts achieved PR and completed a total of 6 cycles of ABVD plus RT in hyper metabolic lesions. Twenty five achieved CR (72%), 5 persisted with PR and 2 died of progressive disease. Four pts showed progressive disease (PD) after 3 ABVD and received ESHAP and ASCT, 2 achieved and remained in CR, 1 is in PR and 1 died of progressive disease. Of 173 pts who completed treatment with ABVD × 3 cycles, ABVD × 6 cycles plus RT on PET-TC positive areas or ESHAP plus ASCT, 164 pts (95%) achieved CR. Of these 164 pts., 14 pts (8%) relapsed. The EFS and OS at 36 months is 83% and 97% respectively. Patients with early negative PET-TC have an event-free survival of 87% compared to 62% (P=0,001) for pts with early positive PET CT. The OS at 36 months was 100% versus 86% respectively (<0.001). Conclusion: Treating patients with ABVD, evaluating response after 3 cycles with PET-CT, and adapting further therapy, leads to a high rate of CR avoiding more aggressive chemotherapy and radiotherapy. Three courses of ABVD without RT are adequate in patients with early CR defined by negative PET-CT. In early positive PET-CT it is possible to intensify therapy improving the otherwise bad prognosis; more aggressive treatment might also be suitable. These results need to be confirmed by a larger group of patients and a longer follow-up. Disclosures: No relevant conflicts of interest to declare.
The new international (ISS) staging system is easier to compute and a better predictor of surviva... more The new international (ISS) staging system is easier to compute and a better predictor of survival after diagnosis (dx) of MM than the Durie Salmon staging system (DSS). It is not known if either system predicts treatment failure following upfront AuHCT. We compared the ISS vs DSS at dx for predicting progression free survival (PFS) after AuHCT. The outcomes of 729 recipients of AuHCT done ≤12 months of dx reported to the CIBMTR between 1995–2002 were analyzed. Treatment failure (progression or death) after AuHCT was modeled using Cox proportional hazards regression. Risk factors considered were age, gender, Karnofsky score, immunochemical subtype, number of lines of chemotherapy, chemotherapy sensitivity, disease status pre transplant, serum creatinine, time from dx to transplant and year of transplant. Cox models were then fit with DSS and ISS stages in addition to covariates identified as significant. The percentage of explained variability (R2) was calculated using Brier scores. The Brier score estimates the predictive performance of prognostic schemes for survival data. A smaller Brier score and a larger R2 indicate better predictive performance. 61% of patients were male; 62% had performance scores ≥90 and 82% had chemosensitive disease. Single (91%) or tandem (9%) AuHCT was performed at a median of seven mo after dx; 73% used melphalan-based regimens. With a median follow up of 56 mo after AuHCT, univariate probabilities of treatment related mortality (TRM), relapse, PFS and overall survival at 5 years were 7 (95% confidence interval [CI], 5–9)%, 68 (64–72)%, 25 (21–29)% and 52 (47–56)%, respectively. In multivariate analysis, significant risk factors for treatment failure were resistance to chemotherapy pre transplant, no remission pre transplant and longer delay from dx to transplant. Most patients were in DSS stage III (62%). Patients were more evenly distributed across the 3 ISS stages; only 36% were concordant between systems (Table 1). Cohen’s kappa (a measure of agreement between scores) indicated little concordance between DSS and ISS (K=0.09 [95% CI: 0.04–0.13]). Both systems suggested patients well for PFS and OS. Median PFS times for stages I, II and III by DSS and ISS systems were 58, 31, 24 mo and 33, 27 and 23 mo, respectively. Corresponding median survival times for stages I, II, III by DSS and ISS were 82, 68, 50 and 64, 68, 45 mo, respectively. Compared to the ISS, DSS demonstrated a lower BS and higher R2 (Table 2) consistent with a marginally superior predictive ability for 1, 3 and 5 year PFS (Figure). However, neither system is strongly predictive of outcome after AuHCT since the R2 (measure of explained variability) is low (<5%) for both systems - indicating the need for newer schemes that incorporate other predictors, e.g. cytogenetics. Table 1 ISS, N(%) DS, N(%) I II III I 26 (4) 20 (3) 4 (1) II 92 (13) 104 (14) 34 (5) III 134 (18) 183 (25) 132 (18) Table 2 BS R2,% Time DSS ISS DSS ISS 1 year 0.1855 0.1860 4.1 3.9 3 years 0.2323 0.2343 4.2 3.4 5 years 0.1818 0.1846 2.7 1.2 Figure Figure
Background: Obesity is increasing in prevalence worldwide and has potential implications on chemo... more Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5– 24.9), overweight (25–29.9), obese (30–34.9), or severely obese (≥35). Underweight patients (BMI <18.5, N=9) were excluded from analysis. We analyzed overall survival (OS) and progression-free survival (PFS) from date of transplant, using Kaplan-Meier curves and the log-rank test for univariate analyses and using Cox proportional hazards models for multivariate analyses. Results: Cases were reported from 114 centers in 10 countries. There were 292 patients of normal weight (27%); 472 were overweight (43%), 198 were obese (18%), and 125 severely obese (11%). Median follow-up of survivors was 63, 61, 60 and 59 months, respectively. Significant baseline differences among BMI groups indicate that obese patients selected for transplant were younger (median age 58, 58, 56, and 55 years, respectively, p=0.005) and had less severe disease at diagnosis, with lower bone marrow plasmacytosis and less frequent renal failure, hypercalcemia, and severe anemia. Obese patients received higher total melphalan doses but lower doses per square meter of body surface area (calculated based on actual body weight). Univariate analyses show no significant effect of BMI category on either OS or PFS. However, among patients who received TBI as part of conditioning, multivariable analyses show a significant effect of BMI on PFS (p-value for interaction 0.006). In this subgroup, a higher BMI was associated with longer PFS (p=0.006, Figure 1). Among patients who received melphalan alone, no effect of BMI was apparent (Figure 2). The difference in PFS for patients receiving melphalan/TBI was due to a decreased risk of relapse among obese patients. Pairwise comparisons of conditioning regimen (TBI vs. no TBI) within BMI categories showed significant reduction in risk of treatment failure for obese (HR=0.54, p=0.04) and severely obese (HR=0.32, p=0.001) patients who received TBI. No differences in OS were apparent in multivariate analyses. Relative risks (RR) for PFS from a multivariable model adjusting for possible confounders are shown below: TBI No TBI n RR (95% CI) P n RR (95% CI) P Normal 44 1.00 Poverall=0.006 248 1.00 Poverall=0.18 Overweight 62 0.92 (0.60–1.40) 0.69 405 0.90 (0.75–1.08) 0.24 Obese 21 0.49 (0.27–0.90) 0.021 177 0.85 (0.68–1.07) 0.16 Severely obese 22 0.39 (0.20–0.76) 0.005 100 1.12 (0.86–1.45) 0.42 Conclusion: Obesity, when measured by BMI, has no statistically significant effect on OS among patients with myeloma receiving high-dose melphalan. Among patients receiving melphalan with TBI, a higher BMI is associated with improved PFS. The reason for the restriction of this effect to TBI-containing conditioning regimens requires further investigation. The current common strategy of reducing melphalan doses (i.e. calculating based on ideal or adjusted body weight) does not appear to impair outcomes for obese patients. Obesity should not exclude patients from consideration of autologous transplantation. Figure Figure
BACKGROUND: Non-secretory myeloma (NSM), where immunofixation fails to detect a monoclonal protei... more BACKGROUND: Non-secretory myeloma (NSM), where immunofixation fails to detect a monoclonal protein in serum and/or urine, accounts for <5% of cases of multiple myeloma (MM). The outcome of patients with NSM versus SM undergoing AuHCT has not been evaluated in clinical trials and patients with NSM are often excluded from clinical trials of MM therapy. METHODS: We compared the probabilities of treatment-related mortality (TRM), disease progression, progression-free survival (PFS) and overall survival (OS) after AuHCT for patients with NSM versus SM transplant between 1989 and 2003, reported to the CIBMTR. Immunofixation reports were reviewed to confirm the diagnosis of NSM. 110 patients with NSM were matched to 438 patients with SM using a propensity score (PS) approach. PS were calculated using age at transplant, Durie-Salmon stage at diagnosis, sensitivity to pretransplant therapy, time from diagnosis to transplant and year of transplant. A logistic regression model was fit and a numerical score derived for each case (NSM recipients). Controls (SM) were matched in random order to cases with similar PS. Multivariate Cox proportional hazards regression models were stratified on matched pairs. Recipients who had a planned second transplant (whether they received their 2nd transplant or not) were excluded. RESULTS: The two groups were similar with respect to disease characteristics at diagnosis (bone marrow plasmacytosis, ISS, renal function) and at transplant (performance status,β2-microglobulin, prior therapy and presence of bone disease). Patients with SM were more anemic and had lower serum albumin levels at diagnosis, while those with NSM were more likely to have preceding plasmacytoma and radiation therapy, presumably to the plasmacytoma. 5-year outcomes, with a median follow-up of 66 months (range, 1 – 177) were as follows: Outcome, Probability (95% CI) NSM SM P-value TRM, % 8 (3 – 14) 7 (5 – 10) 0.86 Disease progression, % 65 (55 – 75) 72 (67 – 76) 0.21 PFS, % 27 (18 – 37) 20 (16 – 25) 0.20 OS, % 51 (40 – 67) 43 (38 – 48) 0.22 In multivariate analysis, based on a Cox model stratified on matched pairs and adjusted for covariates not considered in the propensity score, we found no difference in outcome between the NSM and SM groups. The causes of death were similar between the two groups with disease progression accounting for 75% of deaths. CONCLUSION: In this large cohort of patients undergoing AuHCT, we found no difference in the outcome of patients with NSM compared to those with SM. With increasing use of the free light chain assay, the majority of patients with NSM are expected to have detectable light chain abnormalities thus making them oligosecretory rather than truly non-secretory. This group of patients is generally underrepresented in prospective clinical trials of MM. This study establishes that the post transplant outcomes of this subset of patients are not different and suggests that they should not be excluded from clinical trials.
Background. In our experience, in Argentina, the use of rituximab + chemotherapy in relapsed/refr... more Background. In our experience, in Argentina, the use of rituximab + chemotherapy in relapsed/refractory CD20+ follicular (FL) non-Hodgkin’s lymphoma results in <1 year progression-free survival. 90Y-Zevalin® (90Y-ibritumomab tiuxetan), a radiolabeled antibody to CD20, has shown promising activity in this patient population. We present the initial outcome of a phase 2 trial conducted by the Argentinean Cooperative Group, using 90Y-Zevalin for relapsed refractory FL and transformed lymphomas. Methods. Between September 2005 and November 2005, we recruited 10 patients (pts; 6 male/4 female; median age = 56 yr [range: 45–71 yr]) with platelets >100,000/mm3 and bone marrow involvement <25% for this trial. Nine pts had FL and 1 pt had mantle cell lymphoma. Four pts had bulky disease (largest diameter >5 cm). Three pts were Ann Arbor stage I or II and 7 pts were stage IV. Three pts had received 1–2 cycles of rituximab + chemotherapy and 7 pts had received 3–5 previous cycles. Three pts had undergone autologous transplant. Pts received rituximab 250 mg/m2 IV on days 0 and 7. After the second dose of rituximab, pts received 11 MBq (0.3 mCi) 90Y-Zevalin per kg or 15 MBq (0.4 mCi) 90Y-Zevalin per kg based on platelet counts, with a maximum dose of 32 mCi. Blood counts were monitored weekly until week 10 post-treatment and monthly thereafter. Patient tumor response was reevaluated 3 and 6 months after treatment according to standard criteria. Results. Five pts received a complete dose of 0.4 mCi 90Y-Zevalin per kg and 5 received a reduced dose of 0.3 mCi 90Y-Zevalin per kg. The overall response rate was 60% (CR = 5, PR = 1). Table 1 summarizes the responses. The 5 pts with a CR remained disease-free 8 months later. The pt with a PR progressed with adenopathies and visceromegaly 7 months after treatment. Seven of 10 pts experienced hematologic toxicity: 5 of these 7 pts required G-CSF because of grade 3/4 neutropenia and 3 of these pts developed neutropenic fever. Four of the 7 pts required platelet transfusions and 2 of them required red blood cell transfusions. All 3 pts with previous autologous transplant were in the group with hematologic toxicity. All of these pts required G-CSF and transfusion support, and 2 of these 3 pts were admitted to the clinic for this treatment; hematologic recovery occurred by week 9 post-treatment. Conclusion. The use of 90Y-Zevalin in the relapsed/refractory NHL setting resulted in better response rates and longer disease-free survival than with standard chemoimmunotherapy. Our finding with 50% CR in a heavily pretreated cohort, including 42.8% CR in stage IV pts and 33% CR after autologous transplantation, is encouraging. We are continuing to follow these patients. Table CR PR NR/PD Previous transplant (n=3) 1 1 1 Mantle cell (n=1) 0 0 1 Follicular (n=9) 5 1 3 Tumor volume > 5cm (n=4) 1 0 3 Tumor volume <5 cm (n=6) 4 1 1 Stage I or II (n=3) 2 0 1 Stage IV (n=7) 3 1 3
Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PE... more Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PET-CT) is an important tool for treatment response assessment in Hodgkin Lymphoma (HL) treated with ABVD. It can predict response and overall outcome. The negative predictive value for PET-CT in patients (pts.) with HL is 90–94%. New recommendations define complete remission (CR) for HL as the lack of signs and symptoms of lymphoma with a negative PET-CT. OBJECTIVES: Reduce therapy in pts. who achieve early CR with negative PET-CT. Intensify treatment, only in pts. with positive PET-CT after 3 cycles of ABVD. Achieve CR, event free survival (EFS) and overall survival (OS), as good as in our historical control, when we used 3 or 6 cycles of ABVD plus involved field radio therapy (IFRT) in all pts.(LH-96) PATIENTS AND METHOD: Since October 2005, 200 newly diagnosed pts. with HL have been included in a prospective multicenter clinical trial (LH-05) All pts. received 3 cycles of ABVD and were then evaluated with a PET-CT (PET-CT +3) Pts. with a negative PET-CT+3 and absence of other signs or symptoms of lymphoma were considered in CR and received no further therapy. Pts with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions were considered in partial response (PR) and completed 6 cycles of ABVD and IFRT on PET-CT positive areas. Pts with less than PR received high doses of chemotherapy and an autologous stem cell transplant (ASCT). All pts were re-evaluated at the end of treatment with a new PET CT. One hundred and ninety three pts. have been evaluated. The median age at diagnosis was 29 years. One hundred and twenty five (65%) had localized stage (I-II) non bulky and 68 (35%) presented with advanced stage (III-IV), or bulky disease, 33 (17%) had bulky disease. RESULTS: One hundred and forty-eight (77%) achieved CR with negative PET-CT + 3. Forty-five (21%) were PET-CT+3 positive, 5 showed progressive disease. The other 40 pts. were in PR and completed a total of 6 ABVD + IFRT in PET-CT positive areas. Twenty eight achieved CR and 12 persisted with hypermetabolic lesions. Three died of progressive disease. After finishing planned treatment 178 pts. (92%) were in CR. With a median follow up of 39 months the EFS and OS at 36 months is 80% and 97% respectively. Patients with negative PET-CT +3 have an EFS of 86% compared to 61% for pts. with positive PET-CT+3 (P=0,001). We perform a multivariate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET –CT+ 3. This last parameter together with age were the only ones with statistical significance (p=0.001 and 0.046 respectively). When comparing the results LH-05 with LH-96 there is no difference in EFS and OS at 36 months (83% vs. 85% and 97 vs. 96%) but in LH-05 only 23% received 6 cycles of ABVD and IFRT compared to 61% and 100% in LH-96. This reduces the exposure to chemo and radiotherapy. CONCLUSION: With PET-CT adapted therapy after 3 cycles of ABVD, 148 pts.(77%) received only 3 cycles of ABVD as initial therapy with an EFS and OS of 80% and 97% at 36 months. In the Cox regression model, PET-CT at completion of treatment was the most significant factor associated to EFS. In this interim analysis of PET-CT adapted therapy to all stages of HL, treatment with 3 cycles of ABVD can be adequate for pts. with negative PET-CT+3. Continuing with ABVD after a positive PET-CT +3 can be considered insufficient. A longer follow-up and a larger number of pts. are necessary to confirm these results. Disclosures: No relevant conflicts of interest to declare.
Epigenetic therapy with a hypomethylating agent is becoming the standard of care in some intermed... more Epigenetic therapy with a hypomethylating agent is becoming the standard of care in some intermediate and high-risk myelodysplastic syndromes (MDS). The DNA-targeted hypomethylating agent, decitabine (DACOGEN, Janssen Cilag Farmaceutica S.A. and Eisai Inc.), has been approved for patients (pts) with intermediate-1 (INT-1), intermediate-2 (INT-2), and high-risk MDS in Argentina. An alternative regimen with decitabine 20 mg/m2 IV over 1 hour once daily for 5 consecutive days repeating every 4 weeks, permits its use in the outpatient clinic. Clinical and hematological response and safety were analyzed retrospectively for pts with all FAB subtypes of MDS who had received this dosing regimen at 17 centers in our country between July 2007 and June 2008. Inclusion criteria were: ≥18 years of age; de novo or secondary MDS; and International Prognosis Scoring System (IPSS) score ≥0.5. Exclusion criteria were: diagnosis of acute myeloid leukemia (AML) or other progressive malignant disease. Patients with prior therapy were not excluded. The primary endpoint was overall response, assessed by IWG 2006 criteria. Thirty-eight pts were enrolled: median age 67 years; 71% male and 29% female. The diagnosis was de novo MDS in 34 pts (89%) and secondary MDS in 4 (11%). The median time from diagnosis to first dose of decitabine was 7 months. Eastern Cooperative Oncology Group performance status scores were 0 (21%), 1 (47%), 2 (26%) and 3 (5%). IPSS scores were INT-1 (50%), INT-2 (8%), and high-risk (42%). Cytogenetic abnormalities were found in 37% of pts. FAB classification was: RA (21%), RARS (8%), RAEB (18%), RAEB-T (24%) and CMML (29%). A median of 3.5 cycles (range, 1–8) were given. Dosage had to be reduced in 7 pts (18%) due to comorbidity and cytopenias. Overall improvement rate in the intent-to-treat population was 45% (Table), including: 9% complete response (CR), 5% marrow complete response (mCR), 5% partial response (PR) and 26% hematological improvement (HI). Two pts (5%) had stable disease. Four pts (11%) were non-evaluable for response. Most pts had their first hematological response by cycle 2 and their best response by cycle 4. The mean ± SD time to best response was 2.7±3 months. No differences in clinical and hematological response were observed between pts with INT-2/High compared to INT-1 (8/19 and 9/19, respectively); red cell and platelet transfusion requirements resolved during the first 2 cycles in 13/16 and 7/8 pts, respectively. Overall improvement rates were similar in pts with more and less than 1 year since MDS diagnosis (9/18 and 8/20, respectively). Overall survival was 71% during the observational period (up to 11 months). The most frequent adverse events were neutropenia without fever (47%) and with fever (21%), especially during cycle 2, and thrombocytopenia (23%). This study showed prompt clinical activity for an alternative 5-day dosing schedule of decitabine in the outpatient setting and an overall improvement rate of 45%, with an initial response by cycle 2, the best response by cycle 4, and acceptable tolerability. <>Table. Response to 5-Day Decitabine Dosing Schedule IWG 2006 Criteria ITT (N=38) Overall Improvement Rate (CR+mCR+PR+HI) 17 (45%) CR (Complete Response) 3 (9%) mCR (Marrow Complete Response) 2 (5%) PR (Partial Response) 2 (5%) HI (Hematological Improvement) 10 (26%) SD (Stable Disease) 2 (5%) Failure (Progressive Disease or Death) 15 (39%) Non-Evaluable 4 (11%)
Abstract 824 There is no standard therapy for MM relapsing after autologous hematopoietic cell tr... more Abstract 824 There is no standard therapy for MM relapsing after autologous hematopoietic cell transplantation (AHCT). A second AHCT can result in additional progression-free survival (PFS). Nonmyeloablative/reduced intensity conditioning (NST/RIC) allogeneic transplantation (AlloHCT) has the advantages of a tumor-free graft and the potential of a graft-versus-myeloma (GVM) effect. Few studies have compared second AHCT vs. NST/RIC AlloHCT. We compared the outcome of second AHCT or NST/RIC AlloHCTafter relapse from prior AHCT in patients with MM reported to the CIBMTR from 1995–2008. Recipients of planned tandem transplants, AlloHCT for graft failure or second malignancies and myeloablative alloHCT were excluded. 137 patients underwent second AHCT and 152 underwent NST/RIC AlloHCT (32 HLA-identical sibling and 120 unrelated donor). The table below illustrates clinical characteristics and patient outcomes. AlloHCT recipients were significantly younger (median 53 years [yrs] of age vs. 56 yrs in the AHCT cohort (p < 0.001). The groups were similar in Karnofsky performance score (KPS) and gender. Conditioning regimens differed between groups. In the AHCT cohort, 85% were melphalan based. In the NST/RIC alloHCT cohort, 38% received melphalan + other drugs and 24% received total body irradiation +/− other drugs but no melphalan (p <0.001). Time from 1st to 2nd transplant was significantly shorter for the AlloHCT cohort (30 vs. 23 months, p = 0.014). Acute graft-versus-host disease (GVH) was 35% at 60 days while chronic GVHD was 44% at 36 months.Patient CharacteristicsAutologousAllogeneicP-valueNumber of patients137152Age at 2nd transplant, median (range), years56 (28–65)53 (32–65)0.001*Gender Male84 (61)90 (59)0.720Karnofsky Score pre-transplant ≥90%68 (50)76 (50)0.884Time from 1st to 2nd transplant, months, median (range)30 (6–122)23 (6–78)0.014* 6–24 months44 (32)78 (51)0.001* >24 months93 (68)74 (49)OutcomesTreatment-related Mortality (TRM)12 months2 (1–5)13 (8–19)<0.001*60 months4 (2–8)15 (10–21)<0.001*Relapse/Progression12 months51 (43–58)72 (64–79)<0.001*36 months82 (76–88)80 (73–86)0.655Progression-free survival12 months47 (40–54)15 (10–21)<0.001*36 months13 (9–19)6 (3–10)0.038*Overall Survival (OS)12 months83 (77–89)51 (42–58)<0.001*36 months46 (37–54)20 (14–27)<0.001*60 months29 (21–38)9 (5–15)<0.001**Significant difference The most common cause of death in both cohorts was progression of MM. On multivariate analysis risk of death was higher for alloHCT (HR 2.38, p < 0.001), KPS < 90 (HR 1.96, p < 0.001), and year of transplant (2004 or earlier, HR 1.77, p = < 0.001). AlloHCT was associated with significantly higher risk of TRM (HR 7.14, p < 0.001). Durie-Salmon Stage III was associated with a higher risk of relapse (HR 2.70, 95% CI: 1.93–3.80, P<0.001) and treatment failure in the alloHCT group (HR 3.05, 95% CI: 2.20–4.22, p < 0.001). We conclude that patients with MM who underwent NST/RIC alloHCT after AHCT failure experienced higher TRM and lower probability of survival compared with those who received second AHCT. Because genetic risk data were not available for these patients, we cannot exclude the possibility that the alloHCT population was a higher risk population. Despite this limitation, our data demonstrate that the value of alloHCT after relapse from prior AHCT is limited. Disclosures: No relevant conflicts of interest to declare.
In patients with follicular lymphoma and a high tumor burden, the intergroup PRIMA phase III stud... more In patients with follicular lymphoma and a high tumor burden, the intergroup PRIMA phase III study was designed to evaluate the potential benefit of 2 years of rituximab (R) maintenance after response to first line R-chemotherapy induction regimens (patients registered from 12/2004 until 4/2007). At a median follow up of 3 years (Lancet 2011) and 6 years (Blood 2013 122:509), a significant sustained improvement in progression free survival (PFS) was demonstrated in patients receiving R-maintenance; hazard ratios (HR) of 0.55 and 0.58, respectively. We report here the long term results of this study with 4 additional years of follow-up. Patients initially randomized between observation (n=513) and R-maintenance (n=505) were all followed for 7 years after randomization and thereafter until the 31/12/16 after having given an informed consent for this extended follow-up period consisting of a yearly physician visit (imaging procedures were according to local center practices after year ...
Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source... more Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source of concern for specialists who also strive to preserve fertility. We studied whether gonadotropin-releasing hormone (GnRH) analogs could prevent the early onset of ovarian insufficiency postchemotherapy and protect fertility. The patients were divided into three groups: Control group 1 (Group A), premenarchal patients aged 3 to 7.5 years (n = 5), were not given GnRH analogs administered prior to PCT. Postmenarchal patients (Group B), aged 14.7 to 20 years (n = 12) with normal menstrual rhythm and ovulatory cycles, received treatment with GnRH analogs prior to PCT. Control group 2 (Group C), postmenarchal patients aged 15.9 to 20 years (n = 4), received PCT but no GnRH analog protection. All groups received the PCT regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT. In group B, leuprolide acetate inhibition was obtained with a depot injection administered each month before and during treatment with PCT. To accelerate the timing of ovarian regression, a subcutaneous injection (0.2 mg) was administered simultaneously. In Group A, patients had spontaneous menarche between the ages of 12 and 17.9 years, followed by normal menstruation and ovulatory cycles. Three patients became pregnant. After GnRH analog withdrawal, Group B patients continued with normal ovulatory cycles. Two patients became pregnant. Group C patients presented hypergonadotrophic hypoestrogenic amenorrhea. GnRH analog treatment before and during PCT enhances ovarian function and preserves adolescent fertility. The results must be confirmed in a larger study.
Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source... more Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source of concern for specialists who also strive to preserve fertility. We studied whether gonadotropin-releasing hormone (GnRH) analogs could prevent the early onset of ovarian insufficiency postchemotherapy and protect fertility. The patients were divided into three groups: Control group 1 (Group A), premenarchal patients aged 3 to 7.5 years (n = 5), were not given GnRH analogs administered prior to PCT. Postmenarchal patients (Group B), aged 14.7 to 20 years (n = 12) with normal menstrual rhythm and ovulatory cycles, received treatment with GnRH analogs prior to PCT. Control group 2 (Group C), postmenarchal patients aged 15.9 to 20 years (n = 4), received PCT but no GnRH analog protection. All groups received the PCT regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT. In group B, leuprolide acetate inhibition was obtained with a depot injection administered each month before and during treatment with PCT. To accelerate the timing of ovarian regression, a subcutaneous injection (0.2 mg) was administered simultaneously. In Group A, patients had spontaneous menarche between the ages of 12 and 17.9 years, followed by normal menstruation and ovulatory cycles. Three patients became pregnant. After GnRH analog withdrawal, Group B patients continued with normal ovulatory cycles. Two patients became pregnant. Group C patients presented hypergonadotrophic hypoestrogenic amenorrhea. GnRH analog treatment before and during PCT enhances ovarian function and preserves adolescent fertility. The results must be confirmed in a larger study.
Abstract 53 Prior studies have demonstrated a graft-versus-malignancy effect following allogeneic... more Abstract 53 Prior studies have demonstrated a graft-versus-malignancy effect following allogeneic HSCT that is variably linked to acute or chronic GVHD. Although a graft vs. Myeloma (MM) effect has been shown after myeloablative allogeneic HSCT, a higher treatment related mortality (TRM) risk leads to inferior survival compared with autologous HSCT. Non-myeloablative (NMA) and reduced intensity conditioning (RIC) approaches are used to reduce the risk of TRM while preserving the graft vs. MM effect. The clinical benefit of lower intensity conditioning regimens is thus especially dependent on the impact of acute or chronic GVHD on graft vs. MM effect and TRM. We analyzed the outcomes of 177 matched sibling allogeneic HSCT recipients reported to the CIBMTR between 1997 and 2005 following NMA (n=120) or RIC (n=57) performed within 18 months of diagnosis. Median age was 50 (range 24-69) years and 62% were Durie-Salmon Stage III. Tandem autologous followed by allogeneic HSCT (autologous+ allogeneic) recipients (n=105) were more likely to receive NMA conditioning vs. recipients of an upfront allogeneic HSCT (n=72). Majority (98%) received peripheral blood stem cell grafts. Outcomes at a median follow-up of 36 (3 - 98) months are summarized in table 1. In order to assess the impact of GVHD on outcomes, Cox proportional hazards regression models were built with GVHD as the main effect treating it as a time dependent covariate (Table 2). Other covariates in the multivariate models included age, sex, performance status, IgG vs. non IgG myeloma, disease status and chemosensitivity, prior lines of chemotherapy, donor-recipient sex match, NMA vs. RIC and year of transplant. AGVHD was associated with an increased risk of TRM. Tandem autologous + allogeneic HSCT was associated with reduced relapse risk (RR= 0.49, p=0.008). AGVHD had no impact on relapse/progression of MM while cGVHD was associated with a reduced risk of relapse (Figure. 1). The protective effect of cGVHD on relapse was significant in the non IgG MM subgroup. AGVHD had no impact on PFS whereas cGVHD was associated with superior PFS and lower risk of treatment failure. Later year of HSCT was also associated with superior PFS. Overall survival was not affected by cGVHD while recipients of tandem autologous + allogeneic HSCT had a higher mortality in the presence of aGVHD (RR=3.60, p= 0.01). After matched sibling allogeneic HSCT for MM, aGVHD is associated with a higher risk of TRM whereas cGVHD decreases the risk of relapse and improves PFS. The effect of cGVHD may vary with the type of MM with greater impact in non IgG MM. Further study to identify subtypes of MM susceptible to an immune mediated graft vs. MM effect is suggested. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.
Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transp... more Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (auto HCT). However, little information is available regarding the outcome of patients (pts) with the rarer immunoglobulin subtypes IgD and IgM, which represent 2% and 0.5%, respectively, of all MM cases. In addition, IgD MM has been reported previously to have a poorer prognosis, at least after conventional therapy. The CIBMTR conducted a retrospective analysis of MM pts transplanted between 1995–2005 to describe the characteristics and results of auto HCT in IgD (n=36) and IgM (n=11) among 3578 MM patients with auto HCT during this period. Median follow-up of survivors was 41 (range 2–130) months for pts with IgD and 58 (range 5–101) months for those with IgM MM. Among pts with IgD subtype, median age was 52 years (yrs), 67% were male, 36% had a creatinine >2 mg/L, 61% had Durie-Salmon stage III disease at diagnosis and 33% had Kappa Serum Light chain; the corresponding values for IgM pts were 58 yrs, 36%, 73% and 55% respectively. Prior to auto HCT, 75% of IgD pts were chemosensitive and 25% had received >2 lines of chemotherapy, while all IgM pts were chemosensitive and none had received more than 2 lines of prior therapy. Median time from diagnosis to auto HCT was 9 months in both subtypes. The most common conditioning regimen was singleagent melphalan, and all but 1 pt with IgD disease were grafted with blood stem cells. The small sample size precluded multivariate analysis for potential prognostic factors for outcome. Below table summarizes the post-auto HCT results in these pts contrasted with a reference pool of IgG and IgA MM receiving auto HCT in the same time period. Outcomes, probability (95% CI) IgD IgM IgG/IgA (n=36) (n=11) (n=1475) 100-day mortality, % 0 9 ( 0 – 32) 7 (5 – 8) Non MM deaths, % @ 1 yr 0 9 (0 – 32) 5 (4 – 7) @ 3 yrs 3 (0 – 13) 21 (2 – 51) 16 (14 – 18) Relapse/ Progression, % @ 1 yr 21 (9 – 37) 20 (2 – 49) 18 (16 – 20) @ 3 yrs 59 (41 – 76) 32 (8 – 64) 36 (34 – 39) Progression-free survival, % @ 1 yr 79 (63 – 91) 71 (41 – 93) 77 (74 – 79) @ 3 yrs 38 (21 – 56) 47 (17 – 78) 47 (44 – 50) Overall survival, % @ 1 yr 87 (74 – 97) 91 (68 – 100) 79 (77 – 85) @ 3 yrs 69 (51 – 84) 68 (36 – 93) 53 (50 – 57) No striking differences are apparent in the post auto HCT outcomes of patients with IgD and IgM MM. These results are also consistent with published outcomes of pts with IgD/ IgM MM (Wechaleker et al Ann Hematol. 2005 Feb; 84(2):115–7; Maisner et al Bone Marrow Transplant. 2008 Jan; 41(1):51–4).
Abstract 1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an over... more Abstract 1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an overall survival at 5 years of 80%. ABVD can be considered as gold standard for first line treatment for all stages of HL. Dividing patients (pts.) in different prognostic groups has aimed to reduce chemo and radio toxicity in those patients with good prognosis. A negative PET-CT, either early during treatment of ABVD or after completion of it, has shown to be a powerful prognostic tool (Hutchings: Blood 2006; Gallamini: Haematologica 2006). Our cooperative group has an experience with 584 patients with HL in early or advanced stage treated with 3 or 6 cycles of ABVD plus involved field radiotherapy with a complete remission (CR) of 91% and an event free survival (EFS) and overall survival (OS) at 60 months of 79% and 95%.(S Pavlovsky, Clin Lymp My & Leuk, 2010). Aims: Test the efficacy of treatment to all stages of HL adjusted to PET-CT results after 3 cycles of ABVD. Evaluate the outcome of pts. who have a negative PET-CT after 3 cycles of ABVD and receive no further treatment. Intensify therapy only in pts. who have persistent hyper metabolic lesions in PET-CT after 3 cycles of ABVD. Method: Since October 2005, 198 newly diagnosed pts. with HL have been included in a prospective multicenter trial. Initially all patients received 3 cycles of ABVD. After the third cycle, pts. were evaluated with a PET-CT. Those pts. who achieved CR with a negative PET-CT, received no further treatment. Those with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions by PET-TC after 3 ABVD were considered in partial remission (PR) and completed 6 cycles of ABVD and radiotherapy (RT) on PET-CT positive areas. Those patients with less than PR after 3 cycles of ABVD received ESHAP and if CR, high doses of chemotherapy and an autologous stem cell transplant (ASCT). All patients were re-evaluated at the end of treatment. The median follow up is of 30 months (3-62). Results: One hundred and seventy three patients completed three cycles of ABVD followed by a PET-CT. The median age at diagnosis was 29 years. One hundred and thirty-six (79%) had localized stage (I-II) at diagnosis and 37 (21%) presented with advanced stage (III-IV). Of 155 pts. 77 (50%) pts had IPS 0–1, 66 (43%) had IPS 2–3 and 12 (8%) had IPS 4–5. Twenty six (17%) pts. had bulky disease at diagnosis. One hundred and thirty-seven (79%) pts. achieved CR with negative PET-CT after 3 cycles of ABVD. Thirty-six (21%) were PET-CT positive, of them 32 pts achieved PR and completed a total of 6 cycles of ABVD plus RT in hyper metabolic lesions. Twenty five achieved CR (72%), 5 persisted with PR and 2 died of progressive disease. Four pts showed progressive disease (PD) after 3 ABVD and received ESHAP and ASCT, 2 achieved and remained in CR, 1 is in PR and 1 died of progressive disease. Of 173 pts who completed treatment with ABVD × 3 cycles, ABVD × 6 cycles plus RT on PET-TC positive areas or ESHAP plus ASCT, 164 pts (95%) achieved CR. Of these 164 pts., 14 pts (8%) relapsed. The EFS and OS at 36 months is 83% and 97% respectively. Patients with early negative PET-TC have an event-free survival of 87% compared to 62% (P=0,001) for pts with early positive PET CT. The OS at 36 months was 100% versus 86% respectively (<0.001). Conclusion: Treating patients with ABVD, evaluating response after 3 cycles with PET-CT, and adapting further therapy, leads to a high rate of CR avoiding more aggressive chemotherapy and radiotherapy. Three courses of ABVD without RT are adequate in patients with early CR defined by negative PET-CT. In early positive PET-CT it is possible to intensify therapy improving the otherwise bad prognosis; more aggressive treatment might also be suitable. These results need to be confirmed by a larger group of patients and a longer follow-up. Disclosures: No relevant conflicts of interest to declare.
The new international (ISS) staging system is easier to compute and a better predictor of surviva... more The new international (ISS) staging system is easier to compute and a better predictor of survival after diagnosis (dx) of MM than the Durie Salmon staging system (DSS). It is not known if either system predicts treatment failure following upfront AuHCT. We compared the ISS vs DSS at dx for predicting progression free survival (PFS) after AuHCT. The outcomes of 729 recipients of AuHCT done ≤12 months of dx reported to the CIBMTR between 1995–2002 were analyzed. Treatment failure (progression or death) after AuHCT was modeled using Cox proportional hazards regression. Risk factors considered were age, gender, Karnofsky score, immunochemical subtype, number of lines of chemotherapy, chemotherapy sensitivity, disease status pre transplant, serum creatinine, time from dx to transplant and year of transplant. Cox models were then fit with DSS and ISS stages in addition to covariates identified as significant. The percentage of explained variability (R2) was calculated using Brier scores. The Brier score estimates the predictive performance of prognostic schemes for survival data. A smaller Brier score and a larger R2 indicate better predictive performance. 61% of patients were male; 62% had performance scores ≥90 and 82% had chemosensitive disease. Single (91%) or tandem (9%) AuHCT was performed at a median of seven mo after dx; 73% used melphalan-based regimens. With a median follow up of 56 mo after AuHCT, univariate probabilities of treatment related mortality (TRM), relapse, PFS and overall survival at 5 years were 7 (95% confidence interval [CI], 5–9)%, 68 (64–72)%, 25 (21–29)% and 52 (47–56)%, respectively. In multivariate analysis, significant risk factors for treatment failure were resistance to chemotherapy pre transplant, no remission pre transplant and longer delay from dx to transplant. Most patients were in DSS stage III (62%). Patients were more evenly distributed across the 3 ISS stages; only 36% were concordant between systems (Table 1). Cohen’s kappa (a measure of agreement between scores) indicated little concordance between DSS and ISS (K=0.09 [95% CI: 0.04–0.13]). Both systems suggested patients well for PFS and OS. Median PFS times for stages I, II and III by DSS and ISS systems were 58, 31, 24 mo and 33, 27 and 23 mo, respectively. Corresponding median survival times for stages I, II, III by DSS and ISS were 82, 68, 50 and 64, 68, 45 mo, respectively. Compared to the ISS, DSS demonstrated a lower BS and higher R2 (Table 2) consistent with a marginally superior predictive ability for 1, 3 and 5 year PFS (Figure). However, neither system is strongly predictive of outcome after AuHCT since the R2 (measure of explained variability) is low (<5%) for both systems - indicating the need for newer schemes that incorporate other predictors, e.g. cytogenetics. Table 1 ISS, N(%) DS, N(%) I II III I 26 (4) 20 (3) 4 (1) II 92 (13) 104 (14) 34 (5) III 134 (18) 183 (25) 132 (18) Table 2 BS R2,% Time DSS ISS DSS ISS 1 year 0.1855 0.1860 4.1 3.9 3 years 0.2323 0.2343 4.2 3.4 5 years 0.1818 0.1846 2.7 1.2 Figure Figure
Background: Obesity is increasing in prevalence worldwide and has potential implications on chemo... more Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5– 24.9), overweight (25–29.9), obese (30–34.9), or severely obese (≥35). Underweight patients (BMI <18.5, N=9) were excluded from analysis. We analyzed overall survival (OS) and progression-free survival (PFS) from date of transplant, using Kaplan-Meier curves and the log-rank test for univariate analyses and using Cox proportional hazards models for multivariate analyses. Results: Cases were reported from 114 centers in 10 countries. There were 292 patients of normal weight (27%); 472 were overweight (43%), 198 were obese (18%), and 125 severely obese (11%). Median follow-up of survivors was 63, 61, 60 and 59 months, respectively. Significant baseline differences among BMI groups indicate that obese patients selected for transplant were younger (median age 58, 58, 56, and 55 years, respectively, p=0.005) and had less severe disease at diagnosis, with lower bone marrow plasmacytosis and less frequent renal failure, hypercalcemia, and severe anemia. Obese patients received higher total melphalan doses but lower doses per square meter of body surface area (calculated based on actual body weight). Univariate analyses show no significant effect of BMI category on either OS or PFS. However, among patients who received TBI as part of conditioning, multivariable analyses show a significant effect of BMI on PFS (p-value for interaction 0.006). In this subgroup, a higher BMI was associated with longer PFS (p=0.006, Figure 1). Among patients who received melphalan alone, no effect of BMI was apparent (Figure 2). The difference in PFS for patients receiving melphalan/TBI was due to a decreased risk of relapse among obese patients. Pairwise comparisons of conditioning regimen (TBI vs. no TBI) within BMI categories showed significant reduction in risk of treatment failure for obese (HR=0.54, p=0.04) and severely obese (HR=0.32, p=0.001) patients who received TBI. No differences in OS were apparent in multivariate analyses. Relative risks (RR) for PFS from a multivariable model adjusting for possible confounders are shown below: TBI No TBI n RR (95% CI) P n RR (95% CI) P Normal 44 1.00 Poverall=0.006 248 1.00 Poverall=0.18 Overweight 62 0.92 (0.60–1.40) 0.69 405 0.90 (0.75–1.08) 0.24 Obese 21 0.49 (0.27–0.90) 0.021 177 0.85 (0.68–1.07) 0.16 Severely obese 22 0.39 (0.20–0.76) 0.005 100 1.12 (0.86–1.45) 0.42 Conclusion: Obesity, when measured by BMI, has no statistically significant effect on OS among patients with myeloma receiving high-dose melphalan. Among patients receiving melphalan with TBI, a higher BMI is associated with improved PFS. The reason for the restriction of this effect to TBI-containing conditioning regimens requires further investigation. The current common strategy of reducing melphalan doses (i.e. calculating based on ideal or adjusted body weight) does not appear to impair outcomes for obese patients. Obesity should not exclude patients from consideration of autologous transplantation. Figure Figure
BACKGROUND: Non-secretory myeloma (NSM), where immunofixation fails to detect a monoclonal protei... more BACKGROUND: Non-secretory myeloma (NSM), where immunofixation fails to detect a monoclonal protein in serum and/or urine, accounts for <5% of cases of multiple myeloma (MM). The outcome of patients with NSM versus SM undergoing AuHCT has not been evaluated in clinical trials and patients with NSM are often excluded from clinical trials of MM therapy. METHODS: We compared the probabilities of treatment-related mortality (TRM), disease progression, progression-free survival (PFS) and overall survival (OS) after AuHCT for patients with NSM versus SM transplant between 1989 and 2003, reported to the CIBMTR. Immunofixation reports were reviewed to confirm the diagnosis of NSM. 110 patients with NSM were matched to 438 patients with SM using a propensity score (PS) approach. PS were calculated using age at transplant, Durie-Salmon stage at diagnosis, sensitivity to pretransplant therapy, time from diagnosis to transplant and year of transplant. A logistic regression model was fit and a numerical score derived for each case (NSM recipients). Controls (SM) were matched in random order to cases with similar PS. Multivariate Cox proportional hazards regression models were stratified on matched pairs. Recipients who had a planned second transplant (whether they received their 2nd transplant or not) were excluded. RESULTS: The two groups were similar with respect to disease characteristics at diagnosis (bone marrow plasmacytosis, ISS, renal function) and at transplant (performance status,β2-microglobulin, prior therapy and presence of bone disease). Patients with SM were more anemic and had lower serum albumin levels at diagnosis, while those with NSM were more likely to have preceding plasmacytoma and radiation therapy, presumably to the plasmacytoma. 5-year outcomes, with a median follow-up of 66 months (range, 1 – 177) were as follows: Outcome, Probability (95% CI) NSM SM P-value TRM, % 8 (3 – 14) 7 (5 – 10) 0.86 Disease progression, % 65 (55 – 75) 72 (67 – 76) 0.21 PFS, % 27 (18 – 37) 20 (16 – 25) 0.20 OS, % 51 (40 – 67) 43 (38 – 48) 0.22 In multivariate analysis, based on a Cox model stratified on matched pairs and adjusted for covariates not considered in the propensity score, we found no difference in outcome between the NSM and SM groups. The causes of death were similar between the two groups with disease progression accounting for 75% of deaths. CONCLUSION: In this large cohort of patients undergoing AuHCT, we found no difference in the outcome of patients with NSM compared to those with SM. With increasing use of the free light chain assay, the majority of patients with NSM are expected to have detectable light chain abnormalities thus making them oligosecretory rather than truly non-secretory. This group of patients is generally underrepresented in prospective clinical trials of MM. This study establishes that the post transplant outcomes of this subset of patients are not different and suggests that they should not be excluded from clinical trials.
Background. In our experience, in Argentina, the use of rituximab + chemotherapy in relapsed/refr... more Background. In our experience, in Argentina, the use of rituximab + chemotherapy in relapsed/refractory CD20+ follicular (FL) non-Hodgkin’s lymphoma results in <1 year progression-free survival. 90Y-Zevalin® (90Y-ibritumomab tiuxetan), a radiolabeled antibody to CD20, has shown promising activity in this patient population. We present the initial outcome of a phase 2 trial conducted by the Argentinean Cooperative Group, using 90Y-Zevalin for relapsed refractory FL and transformed lymphomas. Methods. Between September 2005 and November 2005, we recruited 10 patients (pts; 6 male/4 female; median age = 56 yr [range: 45–71 yr]) with platelets >100,000/mm3 and bone marrow involvement <25% for this trial. Nine pts had FL and 1 pt had mantle cell lymphoma. Four pts had bulky disease (largest diameter >5 cm). Three pts were Ann Arbor stage I or II and 7 pts were stage IV. Three pts had received 1–2 cycles of rituximab + chemotherapy and 7 pts had received 3–5 previous cycles. Three pts had undergone autologous transplant. Pts received rituximab 250 mg/m2 IV on days 0 and 7. After the second dose of rituximab, pts received 11 MBq (0.3 mCi) 90Y-Zevalin per kg or 15 MBq (0.4 mCi) 90Y-Zevalin per kg based on platelet counts, with a maximum dose of 32 mCi. Blood counts were monitored weekly until week 10 post-treatment and monthly thereafter. Patient tumor response was reevaluated 3 and 6 months after treatment according to standard criteria. Results. Five pts received a complete dose of 0.4 mCi 90Y-Zevalin per kg and 5 received a reduced dose of 0.3 mCi 90Y-Zevalin per kg. The overall response rate was 60% (CR = 5, PR = 1). Table 1 summarizes the responses. The 5 pts with a CR remained disease-free 8 months later. The pt with a PR progressed with adenopathies and visceromegaly 7 months after treatment. Seven of 10 pts experienced hematologic toxicity: 5 of these 7 pts required G-CSF because of grade 3/4 neutropenia and 3 of these pts developed neutropenic fever. Four of the 7 pts required platelet transfusions and 2 of them required red blood cell transfusions. All 3 pts with previous autologous transplant were in the group with hematologic toxicity. All of these pts required G-CSF and transfusion support, and 2 of these 3 pts were admitted to the clinic for this treatment; hematologic recovery occurred by week 9 post-treatment. Conclusion. The use of 90Y-Zevalin in the relapsed/refractory NHL setting resulted in better response rates and longer disease-free survival than with standard chemoimmunotherapy. Our finding with 50% CR in a heavily pretreated cohort, including 42.8% CR in stage IV pts and 33% CR after autologous transplantation, is encouraging. We are continuing to follow these patients. Table CR PR NR/PD Previous transplant (n=3) 1 1 1 Mantle cell (n=1) 0 0 1 Follicular (n=9) 5 1 3 Tumor volume > 5cm (n=4) 1 0 3 Tumor volume <5 cm (n=6) 4 1 1 Stage I or II (n=3) 2 0 1 Stage IV (n=7) 3 1 3
Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PE... more Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PET-CT) is an important tool for treatment response assessment in Hodgkin Lymphoma (HL) treated with ABVD. It can predict response and overall outcome. The negative predictive value for PET-CT in patients (pts.) with HL is 90–94%. New recommendations define complete remission (CR) for HL as the lack of signs and symptoms of lymphoma with a negative PET-CT. OBJECTIVES: Reduce therapy in pts. who achieve early CR with negative PET-CT. Intensify treatment, only in pts. with positive PET-CT after 3 cycles of ABVD. Achieve CR, event free survival (EFS) and overall survival (OS), as good as in our historical control, when we used 3 or 6 cycles of ABVD plus involved field radio therapy (IFRT) in all pts.(LH-96) PATIENTS AND METHOD: Since October 2005, 200 newly diagnosed pts. with HL have been included in a prospective multicenter clinical trial (LH-05) All pts. received 3 cycles of ABVD and were then evaluated with a PET-CT (PET-CT +3) Pts. with a negative PET-CT+3 and absence of other signs or symptoms of lymphoma were considered in CR and received no further therapy. Pts with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions were considered in partial response (PR) and completed 6 cycles of ABVD and IFRT on PET-CT positive areas. Pts with less than PR received high doses of chemotherapy and an autologous stem cell transplant (ASCT). All pts were re-evaluated at the end of treatment with a new PET CT. One hundred and ninety three pts. have been evaluated. The median age at diagnosis was 29 years. One hundred and twenty five (65%) had localized stage (I-II) non bulky and 68 (35%) presented with advanced stage (III-IV), or bulky disease, 33 (17%) had bulky disease. RESULTS: One hundred and forty-eight (77%) achieved CR with negative PET-CT + 3. Forty-five (21%) were PET-CT+3 positive, 5 showed progressive disease. The other 40 pts. were in PR and completed a total of 6 ABVD + IFRT in PET-CT positive areas. Twenty eight achieved CR and 12 persisted with hypermetabolic lesions. Three died of progressive disease. After finishing planned treatment 178 pts. (92%) were in CR. With a median follow up of 39 months the EFS and OS at 36 months is 80% and 97% respectively. Patients with negative PET-CT +3 have an EFS of 86% compared to 61% for pts. with positive PET-CT+3 (P=0,001). We perform a multivariate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET –CT+ 3. This last parameter together with age were the only ones with statistical significance (p=0.001 and 0.046 respectively). When comparing the results LH-05 with LH-96 there is no difference in EFS and OS at 36 months (83% vs. 85% and 97 vs. 96%) but in LH-05 only 23% received 6 cycles of ABVD and IFRT compared to 61% and 100% in LH-96. This reduces the exposure to chemo and radiotherapy. CONCLUSION: With PET-CT adapted therapy after 3 cycles of ABVD, 148 pts.(77%) received only 3 cycles of ABVD as initial therapy with an EFS and OS of 80% and 97% at 36 months. In the Cox regression model, PET-CT at completion of treatment was the most significant factor associated to EFS. In this interim analysis of PET-CT adapted therapy to all stages of HL, treatment with 3 cycles of ABVD can be adequate for pts. with negative PET-CT+3. Continuing with ABVD after a positive PET-CT +3 can be considered insufficient. A longer follow-up and a larger number of pts. are necessary to confirm these results. Disclosures: No relevant conflicts of interest to declare.
Epigenetic therapy with a hypomethylating agent is becoming the standard of care in some intermed... more Epigenetic therapy with a hypomethylating agent is becoming the standard of care in some intermediate and high-risk myelodysplastic syndromes (MDS). The DNA-targeted hypomethylating agent, decitabine (DACOGEN, Janssen Cilag Farmaceutica S.A. and Eisai Inc.), has been approved for patients (pts) with intermediate-1 (INT-1), intermediate-2 (INT-2), and high-risk MDS in Argentina. An alternative regimen with decitabine 20 mg/m2 IV over 1 hour once daily for 5 consecutive days repeating every 4 weeks, permits its use in the outpatient clinic. Clinical and hematological response and safety were analyzed retrospectively for pts with all FAB subtypes of MDS who had received this dosing regimen at 17 centers in our country between July 2007 and June 2008. Inclusion criteria were: ≥18 years of age; de novo or secondary MDS; and International Prognosis Scoring System (IPSS) score ≥0.5. Exclusion criteria were: diagnosis of acute myeloid leukemia (AML) or other progressive malignant disease. Patients with prior therapy were not excluded. The primary endpoint was overall response, assessed by IWG 2006 criteria. Thirty-eight pts were enrolled: median age 67 years; 71% male and 29% female. The diagnosis was de novo MDS in 34 pts (89%) and secondary MDS in 4 (11%). The median time from diagnosis to first dose of decitabine was 7 months. Eastern Cooperative Oncology Group performance status scores were 0 (21%), 1 (47%), 2 (26%) and 3 (5%). IPSS scores were INT-1 (50%), INT-2 (8%), and high-risk (42%). Cytogenetic abnormalities were found in 37% of pts. FAB classification was: RA (21%), RARS (8%), RAEB (18%), RAEB-T (24%) and CMML (29%). A median of 3.5 cycles (range, 1–8) were given. Dosage had to be reduced in 7 pts (18%) due to comorbidity and cytopenias. Overall improvement rate in the intent-to-treat population was 45% (Table), including: 9% complete response (CR), 5% marrow complete response (mCR), 5% partial response (PR) and 26% hematological improvement (HI). Two pts (5%) had stable disease. Four pts (11%) were non-evaluable for response. Most pts had their first hematological response by cycle 2 and their best response by cycle 4. The mean ± SD time to best response was 2.7±3 months. No differences in clinical and hematological response were observed between pts with INT-2/High compared to INT-1 (8/19 and 9/19, respectively); red cell and platelet transfusion requirements resolved during the first 2 cycles in 13/16 and 7/8 pts, respectively. Overall improvement rates were similar in pts with more and less than 1 year since MDS diagnosis (9/18 and 8/20, respectively). Overall survival was 71% during the observational period (up to 11 months). The most frequent adverse events were neutropenia without fever (47%) and with fever (21%), especially during cycle 2, and thrombocytopenia (23%). This study showed prompt clinical activity for an alternative 5-day dosing schedule of decitabine in the outpatient setting and an overall improvement rate of 45%, with an initial response by cycle 2, the best response by cycle 4, and acceptable tolerability. <>Table. Response to 5-Day Decitabine Dosing Schedule IWG 2006 Criteria ITT (N=38) Overall Improvement Rate (CR+mCR+PR+HI) 17 (45%) CR (Complete Response) 3 (9%) mCR (Marrow Complete Response) 2 (5%) PR (Partial Response) 2 (5%) HI (Hematological Improvement) 10 (26%) SD (Stable Disease) 2 (5%) Failure (Progressive Disease or Death) 15 (39%) Non-Evaluable 4 (11%)
Abstract 824 There is no standard therapy for MM relapsing after autologous hematopoietic cell tr... more Abstract 824 There is no standard therapy for MM relapsing after autologous hematopoietic cell transplantation (AHCT). A second AHCT can result in additional progression-free survival (PFS). Nonmyeloablative/reduced intensity conditioning (NST/RIC) allogeneic transplantation (AlloHCT) has the advantages of a tumor-free graft and the potential of a graft-versus-myeloma (GVM) effect. Few studies have compared second AHCT vs. NST/RIC AlloHCT. We compared the outcome of second AHCT or NST/RIC AlloHCTafter relapse from prior AHCT in patients with MM reported to the CIBMTR from 1995–2008. Recipients of planned tandem transplants, AlloHCT for graft failure or second malignancies and myeloablative alloHCT were excluded. 137 patients underwent second AHCT and 152 underwent NST/RIC AlloHCT (32 HLA-identical sibling and 120 unrelated donor). The table below illustrates clinical characteristics and patient outcomes. AlloHCT recipients were significantly younger (median 53 years [yrs] of age vs. 56 yrs in the AHCT cohort (p < 0.001). The groups were similar in Karnofsky performance score (KPS) and gender. Conditioning regimens differed between groups. In the AHCT cohort, 85% were melphalan based. In the NST/RIC alloHCT cohort, 38% received melphalan + other drugs and 24% received total body irradiation +/− other drugs but no melphalan (p <0.001). Time from 1st to 2nd transplant was significantly shorter for the AlloHCT cohort (30 vs. 23 months, p = 0.014). Acute graft-versus-host disease (GVH) was 35% at 60 days while chronic GVHD was 44% at 36 months.Patient CharacteristicsAutologousAllogeneicP-valueNumber of patients137152Age at 2nd transplant, median (range), years56 (28–65)53 (32–65)0.001*Gender Male84 (61)90 (59)0.720Karnofsky Score pre-transplant ≥90%68 (50)76 (50)0.884Time from 1st to 2nd transplant, months, median (range)30 (6–122)23 (6–78)0.014* 6–24 months44 (32)78 (51)0.001* >24 months93 (68)74 (49)OutcomesTreatment-related Mortality (TRM)12 months2 (1–5)13 (8–19)<0.001*60 months4 (2–8)15 (10–21)<0.001*Relapse/Progression12 months51 (43–58)72 (64–79)<0.001*36 months82 (76–88)80 (73–86)0.655Progression-free survival12 months47 (40–54)15 (10–21)<0.001*36 months13 (9–19)6 (3–10)0.038*Overall Survival (OS)12 months83 (77–89)51 (42–58)<0.001*36 months46 (37–54)20 (14–27)<0.001*60 months29 (21–38)9 (5–15)<0.001**Significant difference The most common cause of death in both cohorts was progression of MM. On multivariate analysis risk of death was higher for alloHCT (HR 2.38, p < 0.001), KPS < 90 (HR 1.96, p < 0.001), and year of transplant (2004 or earlier, HR 1.77, p = < 0.001). AlloHCT was associated with significantly higher risk of TRM (HR 7.14, p < 0.001). Durie-Salmon Stage III was associated with a higher risk of relapse (HR 2.70, 95% CI: 1.93–3.80, P<0.001) and treatment failure in the alloHCT group (HR 3.05, 95% CI: 2.20–4.22, p < 0.001). We conclude that patients with MM who underwent NST/RIC alloHCT after AHCT failure experienced higher TRM and lower probability of survival compared with those who received second AHCT. Because genetic risk data were not available for these patients, we cannot exclude the possibility that the alloHCT population was a higher risk population. Despite this limitation, our data demonstrate that the value of alloHCT after relapse from prior AHCT is limited. Disclosures: No relevant conflicts of interest to declare.
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