Favorable outcomes in elderly patients undergoing high-dose therapy and autologous stem cell transplantation for non-Hodgkin lymphoma.

High-dose therapy and autologous stem cell transplantation (HDT-ASCT) can offer potential long-term remission or cure in patients with non-Hodgkin lymphoma (NHL). Limited experience is available on the safety and efficacy of HDT-ASCT in elderly patients. This is a single-center, retrospective study examining outcomes of HDT-ASCT for 202 NHL patients, ages 60 years and older, between January 2001 and December 2012. Overall survival (OS) and progression-free survival (PFS) were analyzed according to age at HDT-ASCT, hematopoietic cell transplantation comorbidity index (HCT-CI), NHL histology, and remission status at the time of HDT-ASCT. The median age was 65 years (range, 60 to 74) and the majority had either diffuse large B cell lymphoma (n = 73, 37%) or mantle cell lymphoma (n = 69, 34%). One hundred and fifteen patients (57%) had high HCT-CI scores at the time of HDT-ASCT. With a median follow-up of 3.6 years (range, 4 to 11.9 years) for survivors, PFS and OS at 3 years were 60% (95% confidence interval [CI], 53% to 68%) and 73% (95% CI, 67% to 80%), respectively. Transplantation-related mortality (TRM) was 4% both at 100 days and at 1 year after HDT-ASCT. Age and HCT-CI score were not associated with OS or PFS, and high HCT-CI did not correlate with TRM. Seven patients (4%) developed secondary myelodysplastic syndrome or acute myeloid leukemia at a median of 35 months (range, 6 to 48) after HDT-ASCT. In this single-center cohort of elderly patients with NHL undergoing HDT-ASCT, this intervention was proven tolerable and effective, with results similar to those of historic controls in younger patients. Our data suggest that age alone should not preclude HDT-ASCT in elderly patients.

A multicentre study of primary breast diffuse large B-cell lymphoma in the rituximab era.

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4·5 years (range 0·6-20·6 years), the Kaplan-Meier estimated median progression-free survival was 10·4 years (95% confidence interval [CI] 5·8-14·9 years), and the median overall survival was 14·6 years (95% CI 10·2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival.

False-Positive [18F]fluorodeoxyglucose-avid lymph nodes on positron emission tomography-computed tomography after allogeneic but not autologous stem-cell transplantation in patients with lymphoma.

PURPOSE: Determine the clinical significance of [(18)F]fluorodeoxyglucose (FDG)-avid lesions in patients with lymphoma treated with stem-cell transplantation. METHODS: All patients who underwent stem-cell transplantation for lymphoma at Memorial Sloan-Kettering Cancer Center between January 2005 and December 2009 and had post-transplantation FDG positron emission tomography/computed tomography (PET/CT) examinations were included. PET/CT examinations were evaluated for FDG-avid lesions suggestive of disease. Clinical records, biopsy results, and subsequent imaging examinations were evaluated for malignancy. RESULTS: Two hundred fifty-one patients were identified, 107 with allogeneic and 144 with autologous stem-cell transplantation. Of allogeneic stem-cell transplantation recipients, 50 had FDG-avid lesions suggestive of lymphoma, defined as FDG-avidity greater than liver background. However, only 29 of these 50 demonstrated lymphoma on biopsy, whereas biopsy attempts were benign in the other 21 patients. Sensitivity analysis determined that a 1.5-cm short axis nodal measurement distinguished patients with malignant from nonmalignant biopsies. In 21 of 22 patients with FDG-avid lymph nodes ≤ 1.5 cm, biopsy attempts were benign. In the absence of treatment, these nodes either resolved or were stable on repeat imaging. Disease-free survival of patients with FDG-avid ≤ 1.5 cm lymph nodes was comparable with patients without FDG-avid lesions. In comparison, autologous stem-cell transplantation patients rarely demonstrated FDG-avid lesions suggestive of disease without malignant pathology. CONCLUSION: Twenty percent (21 of 107) of patients with an allogeneic stem-cell transplantation demonstrated FDG-avid lymph nodes up to 1.5 cm in short axis on PET/CT, which did not represent active lymphoma. After allogeneic stem-cell transplantation of patients with lymphoma, benign FDG-avid ≤ 1.5 cm lymph nodes can mimic malignancy.

Association of quantitative assessment of the intrafollicular proliferation index with outcome in follicular lymphoma.

The role of the proliferation index (PI) as an outcome predictor in follicular lymphoma (FL) isn't clear. We have previously demonstrated that quantitative image analysis (QIA) is a robust tool for PI determination and the present study aimed to determine the significance of the PI for outcome in low-grade FL. One hundred and twenty-nine patients with grade 1-2 FL were retrospectively analysed. Slides were scanned digitally and follicle/tumour-involved areas were annotated. The intrafollicular PI was estimated by analysing a median of 10 follicles per case. Patients were divided into two groups: PI < 30%, PI ≥ 30% and clinical outcome was analysed. Among the 129 patients analysed, intrafollicular PI ranged from 0·6 to 63·2% with a median of 23·3%. Overall survival was not influenced by PI group. Among those patients initially observed, intrafollicular PI < 30% was associated with longer time to first therapy compared to patients with a PI ≥ 30%. In the group of patients that were treated at diagnosis, PI was not predictive of time to treatment failure (TTTF). Intrafollicular PI is an important predicator of TTFT for patients who are candidates for observation. Further confirmation in an independent cohort of patients is necessary to determine the clinical validity of the results.

A retrospective analysis of peripheral T-cell lymphoma treated with the intention to transplant in the first remission.

BACKGROUND: Peripheral T-cell lymphomas are aggressive lymphomas that have no standard treatment. Studies suggest that HD-ASCT in the first CR improves outcome. Few data exist regarding allo-HSCT in the first CR. PATIENTS AND METHODS: We retrospectively identified patients (2001-2011) with PTCL-not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, initially treated with CHOP, CHOP-ICE (ifosfamide, carboplatin, etoposide), or other therapy with the intention to transplant in the first CR. Disease characteristics, therapy, progression-free survival (PFS), and OS were evaluated. RESULTS: Sixty-five patients were identified. PFS and OS were 38% and 52%, respectively, at 4 years. CHOP and CHOP-ICE regimens had similar outcomes. Treatment with allo-HSCT and HD-ASCT had OS at 4 years of 66% and 67%, respectively. Patients who did not proceed to transplant had OS of 27%. IPI score ≤ 2 and Prognostic Index for T-cell Lymphomas scores ≤ 1 predicted improved outcome. Combined analysis of interim response to CHOP and IPI score also predicted PFS and OS. CONCLUSION: Our results support consolidation of first CR with transplantation. The addition of etoposide did not improve outcomes. Baseline IPI and interim response to CHOP can predict outcomes and guide decisions about transplantation in first CR in PTCL. Randomized trials are necessary to confirm the efficacy of this approach.

Tumor associated macrophages in relapsed and refractory Hodgkin lymphoma.

BACKGROUND: Growing evidence demonstrates that an increased number of CD68 positive tumor-associated macrophages (TAM) is associated with decreased survival in patients with newly diagnosed classic Hodgkin lymphoma (HL). However, the impact of TAM in relapsed and refractory disease is unknown. DESIGN AND METHODS: To investigate whether the presence of elevated CD68 retains its prognostic significance in the relapsed and refractory setting, we analyzed pre-salvage biopsy specimens of 81 patients with relapsed and refractory HL using a tissue microarray. Scoring of CD68 was based on the percentage of CD68 positive TAM compared to the total number of cells in representative areas. The final percent of CD68 positivity for each case was based on the average of cores available for examination. RESULTS: In a univariate analysis, we found that patients with elevated levels of CD68 positive TAM had inferior overall survival (OS) compared with patients who had lower CD68 levels. For patients undergoing autologous stem cell transplant after salvage treatment, elevated CD68 levels were predictive of both adverse OS and event free survival. However, after adjusting for other variables, increased CD68 positive TAM did not retain prognostic significance in a multivariate model. CONCLUSIONS: In our dataset of primary refractory and relapsed Hodgkin lymphoma biopsy specimens, TAM infiltration is unable to definitively predict outcome. In order to validate these findings, TAM infiltration of relapsed and refractory specimens should be assessed prospectively and paired to initial Hodgkin lymphoma biopsies at diagnosis.

18F-fluorodeoxyglucose positron emission tomography in the staging and prognosis of T cell lymphoma.

We previously reported that (18)F-fluorodeoxyglucose positron emission tomography scan (FDG-PET) is almost universally positive in patients with T cell lymphoma. In the present analysis we examined the impact of FDG-PET on the initial staging of peripheral T cell lymphomas (PTCLs), and the prognostic value of interim FDG-PET. This retrospective analysis identified patients with mature T or natural killer (NK) lymphomas who had PET scans as part of initial staging or staging at relapse [(n = 95) (staging cohort)] in the PTCL database at Memorial Sloan-Kettering Cancer Center. A subset of these patients had repeat PET for interim restaging during initial therapy with curative intent [(n = 50) (interim restaging cohort)]. The frequency of specific T cell histologies included in this analysis were: PTCL not otherwise specified (NOS) (n = 35); angioimmunoblastic T cell lymphoma (AITL) (n = 17); anaplastic large cell lymphoma (ALCL), ALK-1+ (n = 11) and ALK-1- (n = 12); adult T cell lymphoma/leukemia (ATLL) (n = 7); NK/T cell lymphoma (NKTCL) (n = 10); and enteropathy-associated T cell lymphoma (EATL) (n = 3). In the staging cohort, 77 patients were newly diagnosed, and 18 had relapsed disease. Pretreatment FDG-PET was positive in 96% of patients. PET identified additional disease sites in 47/95 patients (50%) when added to conventional staging. Most frequently identified additional sites were: other nodal (n = 24); bone (n = 10); skin (n = 8); nasopharynx (n = 4); spleen (n = 3); and lung (n = 2). However, FDG-PET modified computed tomography (CT)-based staging in only 5/95 patients (5.2%): two patients were upstaged and three patients were downstaged. FDG-PET-based staging did not alter planned treatment for any patient. Interim restaging with PET was performed after a median of 4 cycles of chemotherapy. In this cohort, treatment regimens included cyclophosphamide, doxorubicin, vincristine and prednisone CHOP (n = 19); CHOP/ifosfamide, carboplatin and etoposide (ICE) (n = 26); and other (n = 7). Subsequently, 29 patients were consolidated with either autologous (n = 22) or allogeneic (n = 7) stem cell transplant. After a median follow-up of 3.4 years for surviving patients, those with negative interim PET had superior progression-free survival (PFS) compared to patients with positive interim PET (p = 0.03). There were no differences in overall survival (OS). In PTCL, FDG-PET commonly identifies additional sites of disease but infrequently impacts CT-based staging and does not influence therapy. Interim FDG-PET may predict for PFS. FDG-PET should be integrated into prospective trials to confirm these findings.

Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections.

UNLABELLED: Rituximab targets normal B cells and tumor B cells. We used a unique data-mining tool to identify patients with lymphoma who were treated with rituximab and who had serial pre and post rituximab immunoglobulin concentrations evaluated. After treatment, 39% (69/179) of patients had low levels of immunoglobulin G. Recurrent sinopulmonary infections were seen in 6.6% (14/211). Intravenous immune globulin appeared to reduce the frequency of infection. BACKGROUND: Rituximab has altered the treatment approach to B-cell malignancies and other diseases. Reports consider that rituximab had limited impact on serum immunoglobulins. However, anecdotes suggest that rituximab can cause symptomatic hypogammaglobulinemia. This retrospective study examined the relationship among rituximab, hypogammaglobulinemia, and treatment of symptomatic hypogammaglobulinemia with intravenous immune globulin (IVIG). METHODS: Patients with serial quantitative serum immunoglobulin (SIgG) concentrations before and subsequent to rituximab administration at Memorial Sloan-Kettering Cancer Center were identified. Information regarding rituximab administration, SIgG concentrations, frequency of infection, and administration of IVIG were recorded. RESULTS: Between December 1998 and April 2009, 211 patients with B-cell lymphoma treated with rituximab and with serial SIgG concentrations were identified. One hundred seventy-nine (85%) patients had normal SIgG before rituximab, 32 (15%) had low SIgG. After rituximab use, hypogammaglobulinemia was identified in 38.54% of patients with initially normal SIgG. The risk was greater in patients who received maintenance rituximab. Symptomatic hypogammaglobulinemia that prompted IVIG administration developed in 6.6% of patients. CONCLUSIONS: In this data set, rituximab administration was associated with a high frequency of hypogammaglobulinemia, particularly symptomatic hypogammaglobulinemia, among patients who received multiple courses of rituximab. Baseline and periodic monitoring of SIgGs is appropriate in patients who receive rituximab.

Intensive induction chemotherapy followed by early high-dose therapy and hematopoietic stem cell transplantation results in improved outcome for patients with hepatosplenic T-cell lymphoma: a single institution experience.

INTRODUCTION: Hepatosplenic T-cell lymphoma is a rare form of extranodal non-Hodgkin lymphoma, first recognized as a distinct entity in the Revised European-American Lymphoma classification. Typical presentation includes lymphomatous infiltration of spleen and liver, and peripheral lymphadenopathy is rarely seen. The prognosis is almost uniformly poor, and there are no prospective studies of treatment of HSTCL. PATIENTS AND METHODS: For this report, we conducted a retrospective review of all pts who underwent treatment for HSTCL at our institution. Individual chart review was performed to report clinical presentation, management, and outcome. RESULTS: We identified 14 pts with HSTCL managed at our center, 7 of which remain alive with median follow-up of 65.6 months. Six of 7 received alternative induction chemotherapy regimens such as ICE (ifosfamide, carboplatin, etoposide) or IVAC (ifosfamide, etoposide, high-dose cytarabine) as opposed to CHOP and all surviving pts had proceeded to undergo either autologous or allogeneic SCT. CONCLUSION: Our results suggest that use of non-CHOP induction regimen and early use of high dose therapy and SCT consolidation may translate to improved survival for pts with HSTCL.

ABVD alone and a PET scan complete remission negates the need for radiologic surveillance in early-stage, nonbulky Hodgkin lymphoma.

BACKGROUND: Patients with early-stage, nonbulky classic Hodgkin lymphoma (cHL) undergo intensive posttreatment radiologic surveillance despite having a low risk of disease recurrence. The current study attempted to evaluate the risk of disease recurrence and the value of radiologic surveillance in patients treated with the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone who achieved a complete remission (CR) as noted on posttreatment positron emission tomography (PET). METHODS: Forty-seven patients who underwent therapy with interim and/or posttreatment PET scans were evaluated for disease recurrence during ≥ 24 months of follow-up. Their presenting characteristics and imaging results were assessed and interpreted in relation to clinical outcome. RESULTS: All 47 patients were eligible for analysis. The majority of patients were female (35 patients) with a median age of 28 years (range, 17 years-65 years.). The nodular sclerosing subtype was the predominant histology (41 patients). A total of 34 patients were staged with IIA disease, 6 with IA disease, 6 with IIB disease, and 1 with IIEA disease (lung) (according to Cotswolds modification of the Ann Arbor staging system). All patients completed 6 cycles of planned ABVD therapy and achieved a CR. Two had a positive PET scan (1 interim scan and 1 posttreatment scan); both were biopsy-proven sarcoidosis. Two patients developed disease recurrence at 7 months and 24 months, respectively, after negative interim and posttreatment imaging. One case of recurrence was identified through surveillance imaging and the other was identified simultaneously by the patient and surveillance scan. A total of 45 patients experienced a durable CR; 21 had additional unscheduled imaging/workup during surveillance to investigate symptoms or imaging signs of concern. CONCLUSIONS: Because of a low risk of disease recurrence, posttreatment radiologic surveillance appears to be unnecessary in patients with early-stage, nonbulky (CD20 negative) cHL who achieve a PET-detected CR with the ABVD combination alone. This will reduce cumulative radiation exposure and health care costs in a predominantly young patient population.

Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma.

We previously reported that remission duration < 1 year, extranodal disease, and B symptoms before salvage chemotherapy (SLT) can stratify relapsed or refractory Hodgkin lymphoma (HL) patients into favorable and unfavorable cohorts. In addition, pre-autologous stem cell transplant (ASCT) (18)FDG-PET response to SLT predicts outcome. This phase 2 study uses both pre-SLT prognostic factors and post-SLT FDG-PET response in a risk-adapted approach to improve PFS after high-dose radio-chemotherapy (HDT) and ASCT. The first SLT uses 2 cycles of ICE in a standard or augmented dose (ICE/aICE), followed by restaging FDG-PET scan. Patients with a negative scan received a transplant. If the FDG-PET scan remained positive, patients received 4 biweekly doses of gemcitabine, vinorelbine, and liposomal doxorubicin. Patients without evidence of disease progression proceeded to HDT/ASCT; those with progressive disease were study failures. At a median follow-up of 51 months, EFS analyzed by intent to treat as well as for transplanted patients is 70% and 79%, respectively. Patients transplanted with negative FDG-PET, pre-HDT/ASCT after 1 or 2 SLT programs, had an EFS of > 80%, versus 28.6% for patients with a positive scan (P < .001). This prospective study provides evidence that the goal of SLT in patients with Hodgkin lymphoma should be a negative FDG-PET scan before HDT/ASCT.

Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma.

New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors.

Autologous stem cell transplant for early relapsed/refractory Hodgkin lymphoma: results from two transplant centres.

Prior series have demonstrated that early relapsed (within 1 year) or refractory Hodgkin lymphoma (HL) is associated with poor prognosis. To determine the outcome for patients with early relapsed/refractory HL in the modern era, we combined data from two large transplant centres, Cleveland Clinic Taussig Cancer Institute (CCTCI) and Memorial Sloan-Kettering Cancer Center (MSKCC), and analysed consecutive patients transplanted for relapsed/refractory HL following induction failure or remission durations of <1 year. Two hundred and fourteen patients were analysed and the event-free survival (EFS) and overall survival (OS) at 6 years for all patients were 45% and 55%, respectively. Factors significant for prognosis in multivariate analysis were extranodal disease and bulky disease (≥5 cm). Patients with 0, 1, or 2 risk factors achieved 6 year EFS of 65%, 47%, and 24% and 6 year OS of 81%, 55%, and 27%, respectively. Patients with the sole risk factor of early relapsed/refractory disease achieved good outcomes in this large series; however the presence of bulk and/or extranodal disease significantly reduced EFS and OS. Patients with these additional risk factors are best suited for clinical trials investigating novel salvage regimens and post-transplant maintenance strategies.

Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma.

To identify prognostic factors for patients transplanted for relapsed or refractory Hodgkin lymphoma we carried out a combined analysis of patients followed prospectively on 3 consecutive protocols at Memorial Sloan-Kettering Cancer Center. One hundred fifty-three patients with chemosensitive disease after ICE (ifosfamide, carboplatin, and etoposide)-based salvage therapy (ST) proceeded to high-dose chemoradiotherapy followed by autologous stem cell transplantation (ASCT). Patients were evaluated with computed tomography and functional imaging (gallium or fluorodeoxyglucose-positron emission tomography) prior to ST and again before ASCT. Functional imaging status before ASCT was the only factor significant for event-free survival (EFS) and overall survival by multivariate analysis and clearly identifies poor risk patients (5-year EFS 31% and 75% for FI-positive and negative patients respectively). Administration of involved-field radiotherapy with ASCT was marginally significant for EFS (P = .055). Studies evaluating novel STs, conditioning regimens, post-ASCT maintenance, or allogeneic stem cell transplantation are warranted for patients who fail to normalize pre-ASCT functional imaging.

High-dose chemo-radiotherapy for relapsed or refractory Hodgkin lymphoma and the significance of pre-transplant functional imaging.

We previously reported that three risk factors (RF): initial remission duration <1 year, active B symptoms, and extranodal disease predict outcome in relapsed or refractory Hodgkin lymphoma (HL). Our goal was to improve event-free survival (EFS) for patients with multiple RF and to determine if response to salvage therapy impacted outcome. We conducted a phase II intent-to-treat study of tailored salvage treatment: patients with zero or one RF received standard-dose ifosfamide, carboplatin, and etoposide (ICE); patients with two RF received augmented ICE; patients with three RF received high-dose ICE with stem cell support. This was followed by evaluation with both computed tomography and functional imaging (FI); those with chemosensitive disease underwent high-dose chemoradiotherapy and autologous stem cell transplantation (ASCT). There was no treatment-related mortality. Compared to historical controls this therapy eliminated the difference in EFS between the three prognostic groups. Pre-ASCT FI predicted outcome; 4-year EFS rates was 33% vs. 77% for patients transplanted with positive versus negative FI respectively, P = 0.00004, hazard ratio 4.61. Risk-adapted augmentation of salvage treatment in patients with HL is feasible and improves EFS in poorer-risk patients. Our data suggest that normalisation of FI pre-ASCT predicts outcome, and should be the goal of salvage treatment.