Acquisition of Isochromosome 7 Is a Late Change in the Pathogenesis of Hepatosplenic Lymphoma, Documented On a Case of Adolescent Girl 5 Years After Renal Transplant with Preceding TCR Gamma-Delta Positive LGL Leukemia.

Abstract 5031 Background Post-transplant lymphoproliferative disorders (PTLD) occur in 1-20% of recipients receiving solid organ transplantation. We describe a patient who suffered from hepatosplenic T-cell lymphoma occurring after previous PTLD in a renal transplant recipient. Patient/Methods An 11-yr-old girl underwent kidney transplantation for end-stage Fanconi's nephronophthisis in 2002. In October 2006 significant neutropenia (<200/uL) was firstly detected, without any abnormality in bone marrow (BM) aspirate and without hepato- or splenomegaly. Episodes of neutropenia resolved spontaneously or after enhanced immunosuppression and G-CSF. In January 2007 new episodes of neutropenia and newly significant “monocytosis” were detected in peripheral blood (PB) and BM. Percentage of “monocytes” corresponded with immunophenotypically atypical TCR gamma/delta positive T cells (CD7weakposCD5negCD3bright) in PB and BM. Clonal TCR gamma and delta rearrangements were identified which enabled qPCR minimal residual disease (MRD) assessment. No lymphadenopathy was present, slight hepatosplenomegaly was identified by sonography. Conventional and molecular cytogenetic analyses didn't reveal any chromosomal aberration in PB and BM including changes on chromosome 7. No increased levels of EBV and CMV load by PCR were found. Partial increase of granulocytes and slight decrease of atypical TCR gamma/delta T cells were detected after administration of corticosteroid bolus and mercaptopurin. Three months later she presented with fever, rapidly progressive hepatosplenomegaly and pancytopenia, clinically corresponding with hepatosplenic lymphoma. At this time, newly acquired isochromosome 7q was detected by FISH. Results Initial therapy with campath and fludarabine was ineffective. She didn't respond to the 2nd line treatment (prednisone, vincristine, daunorubicine,asparaginase) and died 2 weeks later from lymphoma progression. Autopsy identified severe hemophagocytosis in the liver. Retrospectively, we identified identical clonal TCR rearrangements in the PB samples from March 2006 (∼0.03% of lymphoma PB MRD level), when neither changes in PB count nor clinical symptoms were found. Conclusion We detected a “pre-lymphoma” phase with clonal expansion of atypical TCR gamma/delta T cells more than 1 year before lymphoma manifestation. The presence of isochromosome 7q was a late change during this lymphoma genesis. Grant support IGA NS/9997-4; IGA NR/9531-3, IGA NS 10480-3, Research Projects MZCR 000064203, MSM0021620813 Disclosures No relevant conflicts of interest to declare.

Combination therapy with alemtuzumab and pentostatin is effective and has acceptable toxicity in patients with T-lymphoid neoplasms

7037 Background: The development of effective therapeutic strategies for T-lymphoid neoplasms has been difficult partly due to the paucity of clinical trials. These neoplasms are generally refractory to traditional chemotherapy regimens. Alemtuzumab and pentostatin have response rates of 50% to 65% when used individually to treat various T-cell leukemias and lymphomas. However, most responses are partial and of limited duration. Methods: We have treated 20 patients (pts) with T-lymphoid malignancies (11 T-PLL, 1 ATL, 1 PTCL, 2 T- ALL, 3 γd-T cell hepatosplenic lymphoma, 2 T-LGL) with a combination of alemtuzumab 30 mg IV, 3 times weekly for up to 3 months and pentostatin 4 mg/m2 weekly×4 followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics were administered during the treatment and for 2 months after its completion. Results: The median age of pts was 57 yrs (range, 22 –79 yrs), median WBC was 43.9×109/L (range 0.6 –279.5 x109/L), and median serum β2M was 4.1 mg/L (range, 1.7 –10.8 mg/L). Four pts had splenomegaly, and 6 lymphadenopathy. Thirteen had prior therapy (median 2). Twelve pts have responded (10 CR, 2 PR) for an overall response rate of 60% (including 8 of 11 T-PLL, 1 of 1 ATL, 0 of 2 T-ALL, 2 of 3γd-T cell hepatosplenic lymphoma, 0 of 1 PTCL and 1 of 2 T-LGL). Monoclonal T-cell receptor chain gene rearrangements were detected by PCR in 18 pts and became negative in 5 of 7 evaluable pts in CR. Median response duration has not been reached (range, 0 to 78 weeks). 3 pts have proceeded to allogeneic stem cell transplant, 4 (1 with ATL, 2 with T-PLL, and 1 with T-LGL) have died from disease progression after a response, and 8 were refractory to therapy. Opportunistic infections included reactivation of CMV in 7 pts, reactivation of HSV in 1 pt, recurrence of pre-existing Serratia pneumonia in 1 pt and Aspergillus pneumonia in 2 pts. Unexplained, marked and sustained pancytopenia occurred in 2 pts. Other toxicities were mainly grade 1 and 2 and included nausea, fever, edema, and shortness of breath. Conclusions: The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections including CMV reactivation are a concern, they may be minimized with adequate prophylactic antibiotic therapy. No significant financial relationships to disclose.

Combination Therapy with Alemtuzumab and Pentostatin Is Effective and Has Acceptable Toxicity in Patients with T-Lymphoid Neoplasms.

The development of effective therapeutic strategies for T-lymphoid neoplasms has been difficult partly due to their rarity and paucity of clinical trials. These neoplasms are generally refractory to traditional chemotherapy regimens and novel therapeutic strategies are needed. Alemtuzumab and pentostatin have response rates of 50% to 65% when used individually to treat various T-cell leukemias and lymphomas. However, most responses are partial and of limited duration. Immunosuppression and risk of opportunistic infections are their principal overlapping toxicities. We have treated 17 patients with T-lymphoid malignancies (10 T-PLL, 1 ATL, 2 T-ALL, 2 γδ-T cell hepatosplenic lymphoma, 2 T-LGL) with a combination of alemtuzumab 30 mg IV, 3 times weekly for up to 3 months and pentostatin 4 mg/m2 weekly × 4 followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics including valacyclovir, fluconazole, and trimethoprim/sulfamethoxazole (or equivalents) were administered during the treatment and for 2 months after its completion. The median age of patients was 57 years (range 22 – 79 years), median white blood count was 54.1 × 109/L (range 0.6 – 279.5 ×109/L), and median serum β2M was 4.0 mg/L (range, 1.7 – 10.8 mg/L). Four patients had splenomegaly (1 to 5 cm), and 5 lymphadenopathy. Eleven had prior therapy (median 2, range 1 to 6 regimens). Eleven patients have responded (8 CR, 3 PR) for an overall response rate of 65% (including 8 of 10 T-PLL, 1 of 1 ATL, 0 of 2 T-ALL, 1 of 2 γδ-T cell hepatosplenic lymphoma and 1 of 2 T-LGL). Monoclonal T-cell receptor chain gene rearrangements were detected by PCR in 16 patients and became negative in 5 of 7 evaluable patients in CR. Median response duration has not been reached (range 0 to 78 weeks). Three patients have proceeded to allogeneic stem cell transplant, 4 (1 with ATL, 2 with T-PLL, and 1 with T-LGL) have died from disease progression after a response, and 6 were refractory to therapy. Opportunistic infections included reactivation of CMV in 6 patients (no disease), reactivation of HSV in 1 patient, recurrence of pre-existing Serratia pneumonia in 1 patient and Aspergillus pneumonia in 2 patients. Unexplained, marked and sustained pancytopenia occurred in 2 patients, 1 with T-LGL and 1 with T-PLL. Other toxicities were mainly grade 1 and 2 and included nausea, fever, fatigue, infusion reactions, edema, and shortness of breath. The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections including CMV reactivation are a concern, they may be minimized with adequate prophylactic antibiotic therapy. Remission duration for patients in CR Remission duration for patients in CR