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

AbstractIntroductionHepatosplenic 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 MethodsFor 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.ResultsWe 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.ConclusionOur 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

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

PIM kinase expression in human lymphomas can influence the outcome of chemotherapy, and blocking cap-dependent translation can reverse PIM-mediated rapamycin resistance in murine lymphomas

Tumor associated macrophages in relapsed and refractory Hodgkin lymphoma

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. 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. 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. 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

Pre-Transplant Evaluation with Both CT and PET Following Second-Line Therapy Is Essential for Predicting Outcome in Patients with Transplant- Eligible Relapsed and Primary Refractory Hodgkin Lymphoma

Abstract The standard treatment for relapsed and primary refractory (rel/ref) Hodgkin lymphoma (HL) for patients (pts) who demonstrate chemosensitivity to second-line chemotherapy (ST) is high dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT). Since 1994, four studies at our institution evaluated ICE (ifosfamide, carboplatin, and etoposide) based salvage therapy followed by HDT-ASCT in rel/ref HL. Chemosensitivity is a requirement for pts to proceed to HDT-ASCT, however the definition of chemosensitivity is broad. We use both functional imaging (gallium or PET) and CT to assess response to ICE; pts with chemosensitive disease fall into three groups: normalization of CT and FI (NRM), residual mass on CT but with negative FI (RM, FI-), and FI positivity regardless of CT finding (FI+). Here we report the outcome for pts who responded to ICE ST and proceeded to HDT-ASCT. Between October 1994 and February 2008, 198 pts received ICE on 1 of 4 consecutive protocols (169 pts) or as per protocol (29 pts) and were deemed transplant-eligible. The median follow-up for surviving patients is 7.4 years. There were 99 male pts and 99 female pts; the median age was 31. With respect to the 3 pre-salvage chemotherapy risk factors (RF) (relapse within 1 year of primary treatment, presence of extranodal disease, and B symptoms): 44 pts had 0 RF, 64 had 1 RF, 75 had 2 RF, and 8 had 3 RF. Bulky disease defined as greater than 5cm or 10cm was present in 60 (30%) and 15 (7.5%) pts respectively. The five year event free survival (EFS) and overall survival (OS) were 69% and 78% respectively. Seventy six (38%) had a NRM response to ST, 73 (37%) had a RM, FI- response, and 49 (25%) were FI+. The 5 year EFS and OS for the three groups were 86% and 93%, 71% and 79%, and 41% and 51% respectively. There was a statistically significant improvement in OS and EFS for the NRM and RM, FI- groups compared to the FI+ group (p<0.0001). Surprisingly, a comparison between the NRM and RM, FI- groups also revealed a statistically significant improvement in EFS and OS for the NRM group (p=0.05 and 0.04 respectively). Response to ICE ST followed by HDT-ASCT is associated with a prolonged EFS and OS. The quality of response to ICE ST had a significant impact on outcome. Both a residual mass with normalized FI and abnormal FI after ST predicts for an inferior outcome following HDT-ASCT. However, residual radiotracer on FI was associated with the poorest outcome in both EFS and OS. CONCLUSION: Outcome cannot be predicted by FI alone since both RM, FI- and FI+ groups had an inferior outcome compared to NRM. The most accurate post treatment evaluation includes both CT and PET. Figure Figur

Normalization of FDG-PET Pre-ASCT with Additional Non-Cross Resistant Chemotherapy Improves EFS in Patients with Relapsed and Primary Refractory Hodgkin Lymphoma-Memorial Sloan Kettering Protocol 04-047

Abstract We have reported that outcome of transplant-eligible patients (pts) with relapsed and primary refractory HL is determined by three pre-second-line chemotherapy (ST) risk factors (RF): remission duration of <1 yr., extranodal disease and B symptoms. In addition, normalization of FDG-PET prior to ASCT is the most important factor predicting favorable EFS. We now report the preliminary results of an ongoing phase II risk-adapted study where HL pts receive the following: Favorable risk (0–1 RF) - one cycle of standard dose ifosfamide, carboplatin and etoposide (ICE) ST followed by one cycle of augmented ICE; unfavorable risk (2-RF)- 2 cycles of augmented ICE. All pts then underwent a restaging FDG-PET and the results determined the next treatment. Pts with a negative FDG-PET went directly to HDT/ASCT; however if the FDG-PET was still positive, pts received an additional four biweekly cycles of gemcitabine (1000 mg/m2), vinorelbine (20 mg/m2) and liposomal doxorubicin (15 mg/m2) (GVD) followed by repeat FDG-PET scan; pts without evidence of progression then received HDT/ASCT. Preceding high-dose chemotherapy and ASCT, patients that were radiation therapy-naive received involved field radiotherapy (IFRT) followed by total lymphoid irradiation. Selected previously irradiated patients received only IFRT. Sixty-two pts are evaluable; median follow-up of surviving pts is 30 months; median age was 35. Forty-eight pts had a remission duration of < 1 yr. of those, 28 had primary refractory disease; 28 had extranodal disease and 11 had B symptoms. All patients had previously failed doxorubicin-based chemotherapy; 18 had received prior radiation; of those, 13 failed in the radiation field. Following first ST chemotherapy with ICE, 3 pts progressed, while 37 pts normalized their FDG-PET scan and currently 31 of these pts are event-free. Twenty-five pts with an improving CT scan after ICE still had a persistently positive FDG-PET; they received the second ST with GVD. Of these, 13 pts normalized their FDG-PET scan and 11 are eventfree; the remaining 12 pts had persistently abnormal FDG-PET scan or progressed; only 4 of them are event-free. There was no difference in outcome between the pts who had normal FDG-PET after ICE (pre-ASCT) and those who achieved a negative FDG-PET scan because of the additional ST with GVD. Both of these cohorts had a statistically significant improvement in EFS compared to pts with a persistently positive FDG-PET. In total 46/62 (65%) pts on this program are currently event-free. One pt died from sepsis. Conclusion: For pts with relapsed and primary refractory HL our evolving strategy is to administer ST until normalization of FDG-PET is achieved prior to HDT/ASCT. Figure Figur