mercaptopurine and Lymphoma--T-Cell

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral T-cell lymphoma. It is associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. Recent reports suggest an excessive number of cases of HSTCL in young patients with Crohn's disease who are treated with thiopurines (azathioprine or 6-mercaptopurine [6-MP]) either in conjunction with or without agents that inhibit tumor necrosis factor-alpha (TNF-alpha). Herein, we describe the case of an 18-year-old man with Crohn's disease who developed HSTCL after 5 years of 6-MP treatment. He died 7 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 28 cases of HSTCL in Crohn's patients. All patients were treated with azathioprine or 6-MP; 22 of 28 (79%) received concomitant treatment with infliximab, and 3 of these 22 patients later received treatment with adalimumab. The median age at diagnosis of HSTCL was 22 years (range, 12-40 years). The median survival for all patients was 8 months (range, 5 days-31+ months), with only 1 patient achieving remission. Additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL and what can be done to prevent and treat this devastating malignancy in young patients with Crohn's disease.

Topics: Adalimumab; Adolescent; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azathioprine; Crohn Disease; Fatal Outcome; Humans; Infliximab; Leukemia-Lymphoma, Adult T-Cell; Liver Neoplasms; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Male; Mercaptopurine; Splenic Neoplasms; Tumor Necrosis Factor-alpha

Topics: Chromosome Disorders; Humans; Inflammatory Bowel Diseases; Lymphoma, T-Cell; Mercaptopurine; Splenic Neoplasms

In study NHL-BFM 90 we investigated the efficacy of an ALL-type treatment without local radiotherapy for childhood T-cell lymphoblastic lymphoma (T-LBL). In particular, the prognostic impact of the speed of tumor regression was evaluated. From April 1990 to March 1995, 105 evaluable patients, 1.1-16.4 years of age, with T-LBL were enrolled into study NHL-BFM 90. Patients with stage I and II received an 8-drug induction followed by a consolidation including high-dose-methotrexate (MTX) and maintenance therapy up to a total therapy duration of 24 months. Patients with stage III and IV received an additional reinduction and cranial radiotherapy (CRT) (12 Gy for prophylaxis) between consolidation and maintenance. Residual tumor after completion of induction had to be resected. No local RT was applied. Patients received intensified chemotherapy if tumor regression on day 33 of induction was <70% or when vital residual tumor was present after the induction phase. With a median follow-up of 6.41 years, pEFS at 5 years is 91.4% (SE+/-2.7%). 101 patients were evaluable for the speed of tumor response. Two patients received intensified therapy due to <70% tumor regression on day 33. Of 19 patients with tumor residues after induction, 2 relapsed as compared to 4 of 80 patients with complete tumor regression. Our data demonstrate that, with intensive ALL-type chemotherapy but no local radiotherapy, an event-free survival rate of 90% can be achieved in childhood T-LBL. Providing tumor regression within 5 weeks is sufficient, tumor remnants after induction have weak prognostic impact.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Austria; Child; Child, Preschool; Combined Modality Therapy; Cranial Irradiation; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Germany; Humans; Immunophenotyping; Infant; Life Tables; Lymphoma, T-Cell; Male; Mercaptopurine; Methotrexate; Neoplasm Staging; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Radiotherapy, Adjuvant; Remission Induction; Thioguanine; Treatment Outcome; Vincristine

The risk of non-Hodgkin's lymphoma (NHL) with tumor necrosis factor alpha (TNF-α) inhibitors is unclear, whether related to concomitant thiopurines usage or due to the underlying inflammatory disease. We sought to review all cases of T-cell NHL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors for all approved indications and examine the risk of T-cell NHL with TNF-α inhibitors in comparison with the use of thiopurines in inflammatory bowel disease (IBD).. The FDA Adverse Event Reporting System (AERS) was queried for all lymphomas following treatment with the following TNF-α inhibitors: infliximab, adalimumab, certolizumab, etanercept, and their trade names. Full reports for T-cell NHL cases were identified using the Freedom of Information Act. In addition, T-cell NHL reported in patients IBD with the use of the thiopurines-azathioprine, 6-mercaptopurine, and their trade names were also collected. A search of MEDLINE was performed for additional T-cell NHL with TNF-α inhibitors or thiopurines, not reported to the FDA but available in published literature. The histological subtypes of T-cell NHL reported with TNF-α inhibitors were compared with reported subtypes in Surveillance Epidemiology and End Results (SEER) -17 registry. Reported risk of T-cell NHL in IBD with TNF-α inhibitors, thiopurines, or concomitant use was calculated using Fisher's exact test using 5-aminosalicylates as control drugs.. A total of 3,130,267 reports were downloaded from the FDA AERS (2003-2010). Ninety-one cases of T-cell NHL with TNF-α inhibitors were identified in the FDA AERS and nine additional cases were identified on MEDLINE search. A total of 38 patients had rheumatoid arthritis, 36 cases had Crohn's disease, 11 had psoriasis, 9 had ulcerative colitis, and 6 had ankylosing spondylitis. Sixty-eight of the cases (68%) involved exposure to both a TNF-α inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-cell lymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-α-inhibitor exposure compared with SEER-17 registry. Nineteen cases of T-cell NHL with thiopurines were identified in the FDA AERS and one additional case on MEDLINE. Reported risk of T-cell NHL was higher with TNF-α inhibitor use in combination with thiopurines (95% confidence interval (CI) 4.98-354.09; P<0.0001) and thiopurines alone (95% CI 8.32-945.38; P<0.0001) but not with TNF-α inhibitor use alone (95% CI 0.13-10.61; P=1.00).. Risk of T-cell NHL is increased with TNF-α inhibitor use in combination with thiopurines but not with TNF-α inhibitors alone.

Topics: Adalimumab; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Azathioprine; Certolizumab Pegol; Drug Therapy, Combination; Etanercept; Female; Humans; Immunoglobulin Fab Fragments; Immunoglobulin G; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Lymphoma, T-Cell; Male; MEDLINE; Mercaptopurine; Middle Aged; Odds Ratio; Polyethylene Glycols; Psoriasis; Receptors, Tumor Necrosis Factor; Risk Factors; SEER Program; Spondylitis, Ankylosing; Tumor Necrosis Factor-alpha; United States; United States Food and Drug Administration

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Crohn Disease; Drug Therapy, Combination; Fatal Outcome; Humans; Immunosuppressive Agents; Infliximab; Lymphoma, T-Cell; Male; Mercaptopurine; Middle Aged

A rare case of primary intestinal T-cell lymphoma (ITL) of an 8-year-old boy is reported. Medium- to large-sized tumor cells were betaF1+, CD3+, CD8+. TIA-1+, but CD4-, CD5-, CD30-, CD56-, CD20-, CD79a-, TdT-, consistent with an intraepithelial lymphocyte (IEL) origin. They showed monoclonal rearrangement of the T-cell receptor gamma-chain and no evidence of EBV infection. No clinical, histologic, laboratory, or genetic evidence of celiac disease was detected. In adults, ITL is often associated with enteropathy and has a very poor outcome. Our patient remains in first remission 30 months after finishing the acute lymphoblastic leukemia protocol COALL-07-03 high risk standard.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Etoposide; Humans; Intestinal Neoplasms; Lymphoma, T-Cell; Male; Mercaptopurine; Methotrexate; Methylprednisolone; Neoplasm Staging; Receptors, Antigen, T-Cell, gamma-delta; Remission Induction; Thioguanine; Vincristine

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare type of T-cell lymphoma of CD3+CD8+ phenotype characterized by deep-seated skin nodules or plaques mimicking panniculitis, a result of neoplastic lymphocytes infiltrating the subcutaneous fatty tissue. We present a case of a 19-month year old boy with SPTCL diagnosed and successfully treated in our institution. Disease first presented with symptoms of high fever and painful erythematous nodule located below the umbilicus. Later on the infiltrates appeared on the face, legs, arms and the back of the body. As the most decisive in obtaining the diagnosis, skin biopsy showed atypical, small to medium-sized lymphatic cells infiltrating the deeper dermal layers as well as the subcutaneous adipous tissue surrounding the adipocytes. Immunohystochemical analysis showed neoplastic lymphocytes positive for CD2, CD3, CD5, CD7, CD8, Tia-1, granzyme B and perforine, and negative for CD20, CD34, TDT and CD56. No infiltration of blood vessels or epidermis was evident. Specific T-cell lymphomas protocol (EURO-LB 02) was then initiated which resulted with rapid regression of all general and local symptoms. The treatment was completed according to schedule and the child is now, 24 months after the initiation of the treatment, in complete remission.

Topics: Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Diagnosis, Differential; Erythema; Humans; Immunophenotyping; Infant; Lymphoma, T-Cell; Male; Mercaptopurine; Methotrexate; Panniculitis; Skin

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Crohn Disease; Female; Humans; Immunocompromised Host; Infliximab; Lymphoma, T-Cell; Male; Mercaptopurine; Young Adult

Topics: Adolescent; Antibodies, Monoclonal; Crohn Disease; Fatal Outcome; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Liver Neoplasms; Lymphoma, T-Cell; Mercaptopurine; Splenic Neoplasms; Tumor Necrosis Factor-alpha

Non-Hodgkin lymphomas (NHL) in children are the second most common malignant tumors in Kuwait. Until 1995 the patients (pts) received institutional protocols. From October 1995 to September 2000 21 children with NHL were treated. Five children were treated by NHL BFM 90 protocol, 7 pts received NHL BFM 95 scheme, and 9 children underwent therapy abroad or according to different types of protocols. The results of a retrospective analysis of NHL BFM 95 protocol in Kuwait are reported. Seven patients diagnosed with NHL--group B: 3 children with Burkitt lymphoma (B-cell NHL) and group A: 4 children with lymphoblastic lymphoma (T-cell NHL)--were treated from October 1995 to September 2000 in the Kuwait Cancer Control Centre according to NHL BFM 95 protocol. Group B consisted of 2 girls and 1 boy; median age at diagnosis was 4 years 8 months, 2 pts classified as stage II and 1 pt as stage III. All patients were assigned to risk group R2. Median follow-up is 2 years 8 months. Group A included 1 girl and 3 boys; median age at diagnosis was 5 years 8 months, 1 pt classified as stage III and 3 pts as stage IV. All patients were assigned to IR group. Median follow-up is 3 years 6 months. In group B all 3 pts are in 1st CR; in group A 3 pts are in 1st CR and 1 pt having Li-Fraumani syndrome died after the 3rd relapse of disease during therapy. In both groups there was no toxic death, myelotoxicity WHO grade III-IV, hepatotoxicity WHO grade II-III. Treatment results of NHL BFM 95 study in our small group of patients are very optimistic. Six patients are in 1st CR and one died due to progression of disease. Despite the small group of patients, the results suggest that NHL BFM 95 protocol is highly effective and safe with regular supportive care.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Dexamethasone; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Humans; Ifosfamide; Infant; Kuwait; Leucovorin; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Male; Mercaptopurine; Mesna; Methotrexate; Neoplasm Staging; Prednisolone; Prednisone; Survival Rate; Thioguanine; Treatment Outcome; Vincristine

A study of the effect of combined antineoplastic drugs in vitro was carried out by microcalorimetric monitoring of the metabolic activity of treated cells. Power-time curves of growing T-lymphoma cell suspensions, treated with single or combined drugs, were recorded. The extent of the effect was evaluated by changes in the slopes of the microcalorimetric curves and the kinetics of the drug action were interpreted from the time at which these changes reached their maximum value. The method was validated using two well-established drug combinations, the potentiatory effect of dipyridamole on methotrexate cytotoxicity, and the synergism between methotrexate and 6-thioguanine. In the first case, where one drug is not toxic, the modulation may be evaluated by comparing the inhibition produced by the toxic drug alone and in combination with its modulator. Otherwise, when both drugs are toxic, the combined effect must be evaluated by means of their combination index. The measurement procedure is simple, the electric signal is well suited to automation of data acquisition and the response may be evaluated within 5 to 6 h of drug administration. Moreover, we demonstrate that microcalorimetry is a reliable method for the detection of modulatory effects in combination chemotherapy.

Topics: Antineoplastic Agents; Calorimetry; Cell Death; Dipyridamole; Drug Synergism; Humans; Kinetics; Lymphoma, T-Cell; Mercaptopurine; Methotrexate; Thioguanine; Tumor Cells, Cultured