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Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed—median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders primarily seen in the elderly that are characterized by ineffective hematopoiesis and a propensity to develop AML. Clinicians may be hesitant to refer older patients with unexplained cytopenias and/or macrocytosis for a bone marrow biopsy (BM), and consequently undiagnosed patients may be deprived access to effective treatments. Previously, we described factors which were independently predictive of a diagnosis of MDS at time of bone marrow: age ≥65, mean cell volume (MCV), red cell distribution width (RDW), and lactate dehydrogenase (LDH), and suggested a scoring system to calculate the post-test probability of MDS [1]. In this study we validate this scoring system in a cohort of 313 individuals who underwent bone marrow examinations for the investigation of unexplained cytopenias and or macrocytosis over a 3 year period at our institution (2006-2008). Thirty-two percent of all patients were diagnosed with MDS and 9% had suspected MDS. The post-test likelihood of a diagnosis of MDS increased from 12% when none of the four identified factors were present to 48% when 3 or more factors were present. This scoring system can be used to guide the diagnostic testing of patients presenting with unexplained cytopenias or macrocytosis.

Although unexplained anemia is common in the elderly, the prevalence of MDS is poorly defined. We reviewed 2267 bone marrows reviewed at our center between the years 2002 and 2005. Of these, 322 met our criteria for inclusion (14%). Seventy-three patients (22.6%) had a confirmed diagnosis of MDS and 32 (9.9%) had suspected MDS. Confirmed or suspected MDS was more likely in patients aged >65 (31.5% and 11%, respectively). Age, MCV, LDH and RDW were independently predictive of MDS. Extrapolation of our findings to the elderly anemic individuals in the community suggests MDS prevalence may be higher than previously postulated.

Chronic myelomonocytic leukemia (CMML) is an uncommon disorder characterized by monocytosis of the peripheral blood, absence of the Philadelphia chromosome, fewer than 20% blasts, and one or more lineages showing dysplastic features. Splenomegaly is frequently seen and may be massive. A 56-year-old man with stable CMML and moderate splenomegaly presented to the emergency department with generalized abdominal pain and abrupt drop in hemoglobin. Abdominal imaging revealed splenic rupture and emergency splenectomy was undertaken, with complete recovery. Atraumatic rupture of the spleen has rarely been reported as a complication of CMML or other myelodysplastic disorders. This report should alert physicians to consider this diagnosis in patients with CMML and acute abdominal pain.

We have studied, as part of a group of international multicenter phase II clinical trials, the toxicity and effectiveness of CAMPATH1H administered intravenously three times a week in an outpatient setting to patients with recurrent or progressive low grade lymphoma. We report here on the toxicity and therapeutic results of the first seven patients treated before the study was closed prematurely because of unacceptable toxicity. Classical complete or partial responses of treatment were seen in three of seven patients. One complete response lasted 8.5 months and the other complete response is ongoing at 1 year. Responses occurred in nodal sites as well as in skin and peripheral blood. The first three or four antibody infusions in each patient was associated with grade 1 or 2 side-effects including rigor, fever, facial flushing, nausea, vomiting, hives, wheezes, hypotension, and/or diarrhea but these subsequently decreased or disappeared. The most significant toxicity was profound lymphopenia and associated infection, usually viral. Six of seven patients had culture or serologically documented infections and four patients had two or more such episodes. All infections responded to temporary discontinuation of antibody therapy and appropriate antiviral or antibiotic agents. We conclude that CAMPATH1H monoclonal antibody has therapeutic activity against low grade non-Hodgkin's lymphoma but that this activity is limited by marked lymphopenia and an unacceptably high frequency of serious infection at the dose and schedule used in this trial.

Background: Although the natural history of follicular lymphoma is indolent with a median overall survival of about 12-15 years, the disease is heterogeneous. The 5 and 10 year overall survival (OS) of low, intermediate and high risk FLIPI is 91%, 78% and 53% and 71%, 51% and 36% using standard rituximab-based treatment. 5-year progression-free survival (PFS) is 80%, 70% and 48% respectively. Methods: Based upon this we conducted an investigator-initiated single-centre Phase II trial of intensified therapy with CHOP-R followed by (90)Y ibritumomab tiuxetan consolidation and 24 months of rituximab maintenance as treatment for patients with intermediate and high-risk newly diagnosed symptomatic follicular lymphoma. 33 patients were enrolled. Results: The addition of (90)Y ibritumomab tiuxetan was well tolerated but resulted in asymptomatic grade 3 or 4 thrombocytopenia and neutropenia in11-36% and 10-24% of patients between weeks 2-8 post (90) Y. After 9 years of follow-up (median follow-up 61 months) the 0S for intermediate and high risk FLIPI was 95% and 78%. The 5 year PFS was 79% and 64% for intermediate and high risk FLIPI, respectively. Responses at three months post consolidation were as follows: 3/33 (9%) achieved CR, 25/33(76%), achieved CRU, 1/33(3%) had PR, and 1/33(3%) had PD. Three patients did not receive (90)Y ibritumomab tiuxetan due to disease progression 2/33(6%), or death 1/33(3%). Of 19 patients who had a molecular marker for their lymphoma, 18 (95%) achieved molecular remissions in peripheral blood with CHOP-R therapy. Nine (47%) of these patients have been recently assessed for MRD and remain in molecular remission. The therapy resulted in decreased levels of IgG, IgM and IgA below the lower normal level in 33%, 40% and 23% of patients respectively post therapy. These levels did not recover in most of these patients. B cells were depleted to undetectable levels during therapy including rituximab maintenance. In 18 evaluable patients only 11 recovered normal B cell counts post maintenance rituximab. There was no correlation between normal B-cell recovery and Ig levels. Many patients with low or no B cell counts had normal IgG levels, whereas some patients who regained normal B cell counts were still unable to reach normal Ig levels. No patient developed human anti-mouse antibody. Immunity to measles, mumps, or rubella was retained post therapy. Patients did not have significant infections or opportunistic infections (although 2 developed Grade 1 shingles post (90)Y ibritumomab tiuxetan) and none required IVIG. Conclusions: We conclude that this intensified regimen is highly active in cyto-reducing lymphoma in high and intermediate risk FLIPI follicular lymphoma patients. The toxicity is tolerable although a significant percentage of patients will end up with persistent asymptomatic reductions in B cells and serum Ig. Only randomized trials will determine whether this regimen enhances outcome over standard of care in this higher risk follicular lymphoma population. References: 1.Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Nooka AK, Nabhan C, Zhou X, Taylor MD, Byrtek M, Miller TP, Friedberg JW, Zelenetz AD, Link BK, Cerhan JR, Dillon H, Sinha R, Shenoy PJ, Levy D, Dawson K, Hirata JH, Flowers CR. Ann Oncol. 2013 Feb;24(2):441-8. doi: 10.1093/annonc/mds429. Epub 2012 Oct 5 2.Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting. van de Schans SA, Steyerberg EW, Nijziel MR, Creemers GJ, Janssen-Heijnen ML, van Spronsen DJ. Ann Oncol. 2009 Oct;20(10):1697-702. doi: 10.1093/annonc/mdp053. Epub 2009 Jun 23. PMID: 19549712 Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding.

We report a patient in whom a cell line of 47,XY,+X,t(1;14)(q21;q32) constitution was found in a lymph node excised from the neck. Histologic examination and immunophenotyping both in situ and by flow cytometry failed to confirm a diagnosis of B-cell lymphoma, but Southern analysis indicated the presence of B-cell clonal expansion. These observations support the concept that primary chromosomal abnormalities occur in clonal expansions in the very earliest stages of tumorigenesis.

Effective spleen-derived humoral responses are essential for protecting hosts from blood-borne pathogens. Increased susceptibility to infection is therefore a risk post-splenectomy but is also associated with smoking, chemotherapy and aging. In fact, decreased vaccine efficacy in the elderly may be due to splenic hypofunction. While investigating the role of sensory nerves in hematopoiesis, we discovered a lymphocytosis phenotype involving the splenic marginal zone (MZ). Dividing red and white pulp in the spleen, the MZ is a specialized micro-anatomic structure facilitating innate and adaptive crosstalk to incoming antigen. Sensory nerves were found to synapse at this site and in mice deficient in the major sensory neurotransmitter substance P (Tac-1-/-), MZs were expanded histologically and confirmed by flow cytometry as an increase involving the IgMhiIgDloCD21hiCD23lo MZ B cell population. Tac-1-/- mice also exhibited splenomegaly with overall Ki-67 proliferation indices of 40% vs. 5% in controls. In the peripheral blood, Tac-1-/- mice had persistent polyclonal pan-B cell lymphocytosis with an absolute increase of 200% relative to wildtype. Aberrant B cell homeostasis had functional consequences as demonstrated by significantly decreased total basal plasma IgG (P Disclosures No relevant conflicts of interest to declare.

OBJECTIVE: The objective of this study was to determine the changes in activated protein C resistance that occur during normal pregnancy. STUDY DESIGN: In this cross-sectional study activated protein C was measured in 128 women with normal pregnancies in the first, second, and third trimesters and in nonpregnant control subjects with 24 to 39 women in each group. In addition, factor V, factor VIII, free protein S, and functional protein C were measured and correlated with activated protein C levels. Polymerase chain reaction for factor V Leiden mutation was performed. RESULTS: There was a significant fall in the activity of activated protein C in the second and third trimesters of pregnancy ( p p = 0.002, R 2 = 0.20). The prevalence of the factor V Leiden mutation was 7.3%. CONCLUSION: Resistance to activated protein C is increased in the second and third trimesters of pregnancy. This is related to the alterations in other coagulation proteins, a phenomenon normally occurring during pregnancy. (Am J Obstet Gynecol 1997;177:162-9.)

Abstract 1357 Introduction: High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) is historically effective treatment for patients with relapsed follicular lymphoma (FL) but relapse is common possibly due to contaminated stem cell grafts or inadequate eradication of primary disease. The addition of immunotherapy to HDT/ASCT may augment “in vivo” graft purging and achieve more effective eradication of minimal residual disease (MRD) post ASCT. This may lead to improved PFS and OS. Methods: We conducted 3 sequential prospective phase 2 trials of HDT/ASCT combined with immunotherapy in patients with relapsed FL from 1997–2010. Protocol 1 (n=13) used a-interferon 3 MU/m2 SC TIW for 2 years post ASCT. Protocol 2 (n=23) used a single infusion of rituximab (R) 375 mg/m2 for ‘in vivo’ purging 3–5 days pre-stem cell collection and 2 sets of 4 weekly R at 2 and 6 months post ASCT respectively. Protocol 3 (n=32) used 3 infusions of R 375 mg/m2 pre stem cell collection, followed by a-interferon 3 MU/m2 SC TIW × 2 years + R 375mg/m2 × 6 weekly infusions post ASCT. Eligibility included adult patients age 18–65 with stage III or IV follicular lymphoma grades 1–3a in first or second relapse. Salvage chemotherapy was either CHOP or DHAP depending on prior anthracycline exposure. High dose therapy was cyclophosphamide, carmustine, and etoposide (CBV). Minimal residual disease (MRD) assessment of t(14; 18) by quantitative PCR was serially performed in blood, PBSC and marrow. Studies were REB approved and all patients gave informed consent. Results: Sixty-eight patients from the 3 trials are included. Median age at study enrolment was 47 (30-71) and patients were a median of 31 mo (9-197) from diagnosis. 54% were male. Median FLIPI score was 2. Median # of prior chemotherapies was 1. Median number of cycles of salvage chemotherapy was 4 (2 - 10). 63 patients proceeded to ASCT. 5 patients were not transplanted either do to disease progression (2), or failed stem cell mobilization (3). Baseline characteristics of the patients enrolled in the three trials were similar, with the exception of rituximab(R) exposure in 22% of the patients in Protocol 3. 4 (6%) patients were lost to follow up. Median time to death or last follow was 84.5 mo (7-166). 32 patients (47%) relapsed and 20 (29%) have died. Median follow up times for each trial were 116, 99 and 57 mo. Actuarial median OS for Protocol 1 was 136 mo from enrolment and has not yet been reached for Protocols 2 and 3. Actuarial median PFS for Protocols 1 and 3 are 49 and 78 mo respectively and has not yet been reached for Protocol 2. MRD assessment by PCR was collected on 48 patients. Compared with study 1, the increased use of R pre SC collection improved in vivo purging by 2 logs. In Protocols 1 and 2, most still had detectable disease in the graft to a sensitivity of 1 cell/100,000. In Protocol 3, 56% had MRD negative apheresis products. 91% of 46 evaluable patients achieved molecular remission post stem cell transplant. Thirteen patients (19%) developed secondary malignancies post ASCT with a median time to malignancy of 88.5 mo (39-144). 1 patient developed 2 distinct malignancies. Secondary malignancies present were: MDS (4), AML (1), ALL (1), basal cell carcinoma (2), squamous cell carcinoma (3), thyroid cancer (1), non small cell lung cancer (1) and adenocarcinoma of unknown origin (1). Five (7%) patients transformed to DLBCL, with a median time to transformation post ASCT of 43.5 mo (17-142). The majority of patients who received rituximab immunotherapy pre and post ASCT developed persistent hypogammaglobulinemia. 17 patients (26%) developed interstitial pneumonitis or >2 respiratory complications post rituximab. 4 patients (6%) require monthly IVIG to treat recurrent respiratory infections. 10 patients (15%) developed herpes zoster 15% and 30% of patients in Protocols 1 and 3 did not complete the 2 years of alpha-IFN post ASCT secondary to one or more of depression, fatigue or cytopenias. Conclusion: HDT + ASCT combined with R +/− a-IFN produces durable PFS and molecular remissions but is associated with prolonged hypogammaglobulinemia and higher rates of interstitial pneumonitis. Three infusions of R pre SC collection achieve higher rates of molecular remission. Compliance with 2 years of a-IFN added to R post ASCT is poor and may not add clinical benefits to R alone. The additional role of HDT/ASCT in the era of R-chemotherapy for FL needs to be explored. Disclosures: No relevant conflicts of interest to declare.

Abstract 2571 Background: Myelodysplastic syndromes (MDS) are clonal hematopoetic stem cell disorders characterized by ineffective hematopoiesis and a propensity to develop AML predicted by conventional scoring systems such as the International Prognostic Scoring System (IPSS). Azacitidine (AZA), a hypomethylating agent is indicated for high and high intermediate IPSS scores based on survival and leukemia-free survival benefits demonstrated in randomized trials (Silverman 2002, 2006, Fenaux 2009). Additionally, improvements in fatigue, dyspnea, physical functioning, affect and psychological distress were demonstrated in the CALGB study (Kornblith 2002). We previously showed that most symptom and functional domains of quality of life (QOL) are impaired in MDS patients measured by several instruments and are primarily determined by Hb and transfusion dependence (Buckstein 2009). With the exception of the CALGB paper, there is a paucity of data assessing the ‘real world' QOL in MDS patients treated with AZA longitudinally. All consented patients with MDS followed at our center have QOL assessed every 3–4 months as part of routine care. We present the QOL scores of patients on AZA as assessed by the EORTC QLQ-C30, EQ-5D and a global fatigue scale. Methods: Clinically significant score differences were considered to be 10 points for the EORTC, and 0.05 for the EQ-5D. Linear regression analysis was used to detect each QOL change over time. Log-transformation was applied for all QOL scores to normalize the distribution. To search for significant predictive factors of each QOL, linear regression analysis (for continuous predictive factors) or Analysis of Variance (for binary predictive factors) was conducted at baseline. A two-sided p-value less than 0.05 was considered statistically significant. Results: 30 patients in our database were/are currently treated with AZA. The median age was 73 years, with 63% being male. Of the 26 patients with measureable IPSS scores, 54% were high/high intermediate risk. Seventy percent had a Hb Of the 19 TD patients only 3 became transfusion independent (TI) on AZA and 3 patients who were TI at baseline became TD. Of the 30 patients, 20 have QOL data available for analysis with a median follow up time of 10 weeks (range 0–80) and an interval duration between QOL assessments of 15.5 weeks. Fourteen out of twenty patients have serial QOL assessments, 5 with two, 9 with three or more. The only clinically significant improvements were observed with the EORTC physical functioning and fatigue subscales but constipation scores were higher and global health status/QOL deteriorated over time (Figure 1). At baseline assessment ferritin ≥ 1000 ug/L was negatively associated with physical functioning (p=.0007), cognitive functioning (p=.0012), global QOL (p=.0048) and global fatigue (p=.0003) while transfusion dependence was not predictive of QOL scores. No significant clinical improvements were detected by linear regression or ANOVA over time, but constipation worsened using both models. The health utilities (determined by the summary score of the EQ-5D) are seen in table 1. Conclusion: Many clinically important function and symptom domains of 3 different QOL instruments have not changed significantly over time in our patients receiving AZA. This is likely explainable by the limited sample size and serial number of assessments in our patients. Our present patient population is higher risk than that tested in the CALGB study and our previous report on the MDS patients in our database. Furthermore, we have yet to see the rates of transfusion independence that might be associated with improved QOL. The negative association of increased ferritin with numerous symptom and function scores may simply be a surrogate for the extent of transfusion dependence. We hope that with longer follow up and larger sample size, we will be able to reproduce the QOL benefits observed in the pivotal CALGB trial (Kornblith 2002). Disclosure: No relevant conflicts of interest to declare.

Abstract 1761 Poster Board I-787 Introduction Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis culminating in peripheral blood cytopenias and a propensity to Acute Myelogenous Leukemia (AML). The gold standard diagnostic test is the bone marrow aspirate and biopsy but clinicians are often hesitant to refer patients with unexplained cytopenias or macrocytosis for this test. Consequently undiagnosed patients are deprived access to effective treatments. Previously (Buckstein et al., Leukemia Research 33 (2009) 1313–1318) we identified factors which were independently predictive of diagnosing MDS at the time of bone marrow, including; age, mean corpuscular volume (MCV), red cell distribution (RDW), and lactate dehydrogenase (LDH). In this current study, we set out to validate our findings and determine the sensitivity and specificity of our scoring system for routine clinical practise. Methods We reviewed all bone marrow reports conducted at a tertiary care center for the years (January through December) 2006–2008 inclusive. Our inclusion criteria included bone marrows done for unexplained cytopenias and/or macrocytosis. We excluded all outside consultative referrals and bone marrows done for staging or remission assessment in patients with pre-existing or strongly suspected hemato-lymphoid diagnoses. In cases where the patient had more than one bone marrow, only the most recent marrow was used. The bone marrows were reviewed by two experienced hematopathologists, and the diagnosis of MDS was made using the WHO and/or FAB classification systems. Marrows were classified as ‘confirmed MDS’, ‘suspected MDS’ or ‘Not MDS’. Electronic patient charts were reviewed to determine the age, MCV, LDH and RDW at the time of diagnostic bone marrow. A factor was considered positive if the age was > 65 or if its value exceeded the upper range of normal for our laboratory standards (MCV > 96 fl, LDH > 250 IU/L, RDW >14.5%). All patients for whom we had 4 recorded factors were then assigned a score that ranged from 0 to 4. We determined the distribution of scores within this population, and the sensitivity and specificity of this scoring method in predicting a histopathological diagnosis of MDS. Results Three-hundred and forty bone marrows met our inclusion criteria, and 289 (85%) had all four factors recorded at the time of diagnosis. The predictive ability of the MDS score is summarized in Table 1. The probability of diagnosing MDS increased from 8% with a score of 0 to 46% with a score of 3 or 4. A similar trend was seen when all 344 marrows were analysed. Our scoring system had high sensitivity (> 96%), when only one predictive factor was present and high specificity (96%) when 4 predictive factors were present at the time of diagnostic marrow. (Table 2) Conclusions In patients with unexplained cytopenias, or macrocytosis undergoing a diagnostic BM test, the pre-test probability of a MDS diagnosis increases as the number of predictive factors increases. The specificity of our MDS score also follows a similar trend. The sensitivity is high with only one positive factor indicating a lower score can be used as a screening tool. We have effectively validated a scoring system that may help clinicians decide on the utility of arranging diagnostic bone marrow examinations for patients with undiagnosed cytopenias and macrocytosis. Disclosures Buckstein: Celgene : Honoraria; Novartis: Honoraria.

High-dose therapy and autologous stem cell transplantation (HDT/ASCT) and rituximab immunotherapy have been increasingly applied in the management of non-Hodgkin’s lymphomas (NHL). Although both approaches have been individually associated with B-cell depletion and hypogammaglobulinemia, the incidence, time course, and predictors of prolonged deficiencies following a combined treatment approach is unknown. Methods: We completed a series of prospective phase II studies of HDT/ASCT combined with rituximab for patients with relapsed follicular lymphoma (FL) or diffuse large B cell lymphoma (DLBCL). In two phase II trials of patients with FL (R/Tx and R-IFN/Tx), patients received 9 infusions of rituximab 375mg/m2 as both an in vivo purge and as maintenance post HDT/ASCT. In a trial with relapsed DLBCL or transformed lymphoma, patients received 8 infusions with rituximab 375mg/m2 only as part of the salvage chemotherapy regimen (R-ESHAP/Tx). Immunoglobulin levels were expressed as percentages with 100% representing the lower limit of normal at the institutional lab. Hypogammaglobulinemia was defined as Results: Fifty-one patients with FL were transplanted and were subsequently treated with maintenance rituximab (R/Tx study) or with maintenance rituximab (MR) and interferon-alpha (R-IFN/Tx). Twenty-six patients with relapsed aggressive-histology lymphoma were transplanted with the R-ESHAP salvage regimen. The mean age of the FL patients was 45 and the mean age of the aggressive-histology lymphoma patients was 49. The median number of prior therapies was 1 (range 1–3) for the FL patients and bone marrow involvement at study entry was present in 63%. The median number of prior therapies was 1 (range 1–5) for the aggressive-histology lymphoma patients and bone marrow involvement was present in 15%. Baseline IgG hypogammaglobulinemia was seen in 18% of patients with relapsed FL and 15% of patients with relapsed DLBCL/transformed lymphoma. Median baseline Ig levels in each study are displayed in Figure 1. Patients with FL undergoing HDT/ASCT and MR (combined R/Tx and R-IFN/Tx studies) had prolonged IgG hypogammaglobulinemia compared to patients with aggressive-histology lymphoma (log-rank p=0.0047; see Figure 2). The median time-to-recovery from hypogammaglobulinemia had not been reached after a median follow-up of 42 months. Similarly, IgM level recovery was delayed in the FL group compared to the aggressive-histology patients (p=.0001), although late recovery was noted for this Ig subtype (median time-to-recovery 36 months post-ASCT). Univariate analyses revealed that persistent hypogammaglobulinemia (at 24 months) was associated with FL histology (vs. DLBCL/transformed; p=0.006), bone marrow involvement at study entry (p=0.008), and hypogammaglobulinemia at study entry (p=0.026). Factors not associated with persistent hypogammaglobulinemia included: number of prior therapies, age, and administration of maintenance interferon-alpha. Post-transplant (>3 months) infections included herpes zoster reactivation (n=7) and pneumonia (n=8). One individual in the R-ESHAP/Tx study died of PCP pneumonia 4 months post HDT/ASCT. A relationship between grade III-IV infections and prolonged hypogammaglobulinemia was not evident on univariate analysis (data not shown). Conclusions: Patients with follicular lymphoma undergoing high dose therapy and stem cell transplantation together with rituximab maintenance are likely to experience a prolonged hypogammaglobulinemia whereas this is less likely with patients with aggressive-histology lymphoma undergoing similar doses of rituximab as part of their salvage therapy. Further research is required to elucidate the relative contributions of disease histology, bone marrow involvement, baseline hypogammaglobulinemia, timing of rituximab infusions or other factors not yet identified. Figure Figure Figure Figure