Form Of Mantle Cell Lymphoma Research Articles

Cost-effectiveness analysis of acalabrutinib in treatment of patients with relapsed/refractory form of mantle cell lymphoma who previously received at least one line of therapy

Objective: to conduct a clinical and economic study of acalabrutinib for the treatment of adult patients with relapsed/refractory form of mantle cell lymphoma who previously received at least one line of therapy in the Russian Federation.Material and methods. Acalabrutinib and ibrutinib were considered as compared treatment options. Based on the adjusted indirect comparison, they were found to be comparable in terms of overall survival and progression-free survival. Therefore, a cost minimization analysis method was selected for the study. Based on results of ACE-LY-004 clinical trial a distributed survival model was developed. The model was used to calculate drug costs over a 3-year horizon. To explore uncertainty in the results of economic evaluations we conducted a sensitivity analysis. A number of patients in the hypothetical cohort who could be further treated with a less expensive drug was determined during a missed opportunity analysis. Both mean life years gained and mean progression-free life years were calculated too.Results. Based on simulations over a 3-year horizon, the mean life years gained were 2.45, and the mean progression-free life years were 1.75. The average costs of acalabrutinib therapy both over 1 year and in total over 3 years were 36.6% lower compared to ibrutinib. So, in the 1st year, the costs for acalabrutinib were 3,546,237,60 rubles, for ibrutinib – 5,591,391,00 rubles (a difference of 2,045,153,40 rubles). Using acalabrutinib for 3 years was associated with costs of 7,252,980,60 rubles compared to 11,435,852,60 rubles for ibrutinib (a decrease of 4,182,872,00 rubles). Univariate multi-way sensitivity analysis showed the robustness of modeling results to price fluctuations in the range ±10%. For a hypothetical cohort of 100 patients, using acalabrutinib instead of the more expensive ibrutinib within the same budget will provide therapy to additional 57 patients per year.Conclusion. The results of the study demonstrated that acalabrutinib compared to ibrutinib for the treatment of adult patients with relapsed/ refractory form of mantle cell lymphoma can reduce costs for the 1st year of therapy by 2,045,153,40 rubles (36.6%), and by 4,182,872,00 rubles (36.6%) for 3 years. Thus, acalabrutinib is the cost-saving option for previously treated adult patients with relapsed/refractory mantle cell lymphoma in the Russian Federation.

A retrospective study analyzing activity of ofatumumab in blastic variant mantle cell lymphoma.

e18500 Background: The blastic variant (BV) form of mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma (NHL) for which no standard of care exists. Ofatumumab is a CD20-directed monoclonal antibody (mAb) FDA approved for the treatment of patients with CLL. We retrospectively studied relapsed BV of MCL in patients treated with regimens containing ofatumumab and previous or concurrent epigenetic therapy (cladribine (2-CdaA) and vorinostat). Methods: BV was confirmed by histopathological patterns, ki-67 proliferation index, immunophenotyping, and t(11;14) by FISH and/or cyclin D1 overexpression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival and complete response. Correlative studies to support the hypothesis that epigenetic modulation of multiple genes in multiple pathways can potentiate the activity of mAbs were performed. Results: Ofatumumab administered to 5 Stage IV BV of MCL patients (Table). 3/5 patients had a radiological complete response, lasting 21.1, 13.4 and 12 months, The other 2 patients had partial response and are on the maintenance. Observed PFS in this cohort is a median 13 months (2.7-20.7). Correlative studies following epigenetic therapy found upregulation of the following genes by RT-PCR: NOXA1 (3/5 patients), CEBP1 (2/5) and EZH2 (2/5). Conclusions: Epigenetic drugs can augment the activity of mAbs. In this case, a more potent mAb improves response in MCL. Correlative studies to support the hypothesis that epigenetic modulation of multiple genes in multiple pathways can potentiate activity of mAbs. The combination of 2-CdA and vorinostat synergistically activates genes silenced by histone deacetylation, histone methylation and DNA methylation and enhances the activity of the mAb ofatumumab. [Table: see text]

Multiple Lymphomatous Polyposis Presenting with Lower Gastointestinal Bleeding

Multiple lymphomatous polyposis is an uncommon disease, which is considered to be an intestinal form of mantle cell lymphoma. We present a case of a 66-year-old African American female who was admitted with a 1-week history of painless hematochezia. She has a history of mantle cell lymphoma that was diagnosed from an axillary lymph node biopsy on a prior admission. She refused chemotherapy at that time and was lost to follow up. On this admission she was initially orthostatic and had a hematocrit of 19. Physical examination was pertinent for mandibular, axillary and inguinal lymphadenopathy and rectal examination revealed dark red blood. NG lavage was clear. After resuscitation, she underwent a colonoscopy, which showed multiple polyps throughout the colon, ranging in size from 3 mm to 5cm. There were no rectal polyps. Some of the larger polyps were friable and oozing blood. There was a moderate amount of fresh blood mixed with clots in the lumen up to the transverse colon. Pathology showed diffuse infiltration of the lamnia propria by a monotonous population of atypical lymphocytes that was consistent with mantle cell lymphoma. In addition to the colonic polyps, CT abdomen also showed enlarged mesenteric and retroperitoneal lymph nodes. The liver, spleen and stomach appeared normal. The patient subsequently underwent a subtotal colectomy with ileo-rectal anastomosis for ongoing bleeding. There were innumerable colonic polyps many of which were hemorrhagic. The small bowel was inspected intra-operatively and found to have no lesions. The uninvolved colonic mucosa was unremarkable. The patient recovered uneventfully and was discharged with follow up in oncology clinic after she agreed to chemotherapy. [figure 1]Figure

Non-multiple lymphomatous polyposis form of mantle cell lymphoma in the gastrointestinal tract

Mantle cell lymphoma (MCL) comprises 2.5%-7% of all non-Hodgkin's lymphomas, and the gastrointestinal tract is involved in about 20% of cases. Multiple lymphomatous polyposis (MLP) is an uncommon disease that is regarded as the intestinal form of MCL. We present a rare case of gastrointestinal MCL without MLP, and demonstrate that rituximab was effective for the treatment of this patient. A 61-year-old man presented with continuous diarrhea and hematochezia for a period of 5 months. Superficial lymph nodes were not palpable, but both tonsilla were enlarged. The level of soluble interleukin (IL)2-receptor was 3480 U/ml (normal <500 U/ml). Colonoscopy showed diffuse redness with erosion, without observation of any venous capillary, with these findings continuing from the rectum to the ileum. Upper gastrointestinal endoscopy showed a slightly rough gastric mucosal surface, and chicken-skin like mucosa was observed in the second portion of the duodenum. Small-to-medium size lymphoma cells were seen histologically from the tonsilla to the rectum. The lymphoma cells were immunohistochemically positive for CD5, CD20, CD79a, and cyclin D1. Polymerase chain reaction analysis revealed a chromosomal translocation t(11;14)(q13;q32) in the bcl-1 gene. We diagnosed this as a case of MCL from these findings. For treatment, the patient received a total of ten courses of combination chemotherapy consisting of cyclophosphamide (1000 mg), doxorubicin (70 mg), vincristine (2 mg) and prednisolone (50 mg) (CHOP), which led to a partial remission. However, 2.5 years later, massive infiltrations of the lymphoma cells were found in the colon and stomach. As the infiltrating lymphoma cells expressed CD20 molecules on their surfaces, the patient was treated with a chimeric anti-CD20 monoclohal antibody, rituximab, which showed significant efficacy, and a second partial remission was achieved.

B‐prolymphocytic leukaemia with t(11;14) revisited: a splenomegalic form of mantle cell lymphoma evolving with leukaemia

We reviewed eight cases that were diagnosed before 1995 with B-prolymphocytic leukaemia (B-PLL) harbouring t(11;14)(q13;q32) and/or cyclin D1 staining. Thirteen B-PLL patients without t(11;14) were selected as controls. Peripheral blood, bone marrow and histological sections were re-examined without cytogenetic information. Final diagnosis was made using morphology, cytogenetics, immunophenotype and immunohistochemistry. Clinical characteristics were similar for both groups except for younger age, male predominance and extranodal involvement in cases with t(11;14). CD5 was more frequently positive in the t(11;14)+ group (80%) than in the t(11;14)- group (31%). Surface membrane immunoglobulin was strongly expressed by all t(11;14)+ cases, but only 45% of t(11;14)- cases. Histopathological and cytological review of cases with t(11;14) showed an infiltrate with a mixture of cells, some resembling prolymphocytes and others with mantle cell lymphoma (MCL) morphology. Blood films of cases with t(11;14) showed features suggestive of B-PLL in three, and in others, a mixture of cells resembling MCL and nucleolated ones; none corresponded to the blastoid form of MCL. We suggest that 'B-PLL' with t(11;14) may represent a splenomegalic form of MCL evolving with leukaemia. These cases illustrate the importance of tissue diagnosis with cyclin D1 staining and fluorescence in situ hybridization analysis in B-cell leukaemia with prolymphocytic features.

The splenic form of mantle cell lymphoma.

To describe the clinical, immunophenotypic and molecular features, as well as the clinical course of patients with unusual presentation of mantle cell lymphoma (MCL) purely located to the spleen. We describe seven patients presented with splenomegaly and a leukemic picture without lymphadenopathy, fulfilling the diagnostic criteria of MCL. In addition to clinical and pathologic features, patients were studied with respect to surface immunophenotype, including adhesion molecule profile, immunohistochemical expression of cyclin-D1 and bcl-1 rearrangement by polymerase chain reaction. Four patients were male and three female. The median palpable spleen size was 15 cm. A preliminary diagnosis of MCL was made, based on blood cell morphology and immunophenotype. All patients underwent splenectomy for therapeutic purposes. Studies done in blood and splenic lymphocytes revealed the following: 7/7 patients were CD19/CD5, CD20 and CD38 positive; CD10 negative and 6/7 CD23 negative. The adhesion molecule expression pattern was consistent in all patients: L-Selectin and CD11c were negative, CD11alpha and CD18 weakly positive and CD54 strongly positive. The median spleen weight was 1775 g. Histology disclosed a cytologic and architectural pattern consistent with MCL. Cyclin-D1 was positive in 6/6 studied patients. Bcl-1 rearrangement was found in 5/7 patients. Splenectomy was applied as the sole treatment and was beneficial in all patients, with median blood values as following: prior to splenectomy, Ht 29.5%, platelets 110 x 10(9)/l, lymphoma cells 5.0 x 10(9)/L, and at 6 months post-splenectomy, Ht 43%, platelets 311 x 10(9)/l and lymphoma cells 3.0 x 10(9)/L. Of the seven patients, two developed progressive disease 11 and 26 months post-splenectomy. The remaining five are in improving clinical and hematological condition without chemotherapy at a median follow up of 20 months. We conclude that this presentation represents a separate form of MCL which requires splenectomy. It remains to be seen whether it carries a better prognosis than classical MCL.

Identification of two subgroups of mantle cell leukemia with distinct clinical and biological features.

Mantle cell leukemia (MCLeu) has been considered as a leukemic form of mantle cell lymphoma (MCL). However, the presence of certain features rarely observed in MCL, such as transformation to prolymphocytic leukemia (PLL) or indolent clinical course, suggests that MCLeu may represent a distinct disorder. Seven cases of MCLeu with t(11;14)(q13;q32) and BCL1-IGH gene rearrangement were ascertained among 140 newly diagnosed chronic B-cell lymphoproliferative disorders with leukemic expression. Comparative genomic hybridization, FISH for specific gene loci, and immunological studies were preformed in them. In comparison with CLL, MCLeu cases had low immunological scores < or =2 with respect to B-CLL (P<0.0001). Expression of CD38 was absent in 43% of MCLeu and in 44% of B-CLL. Comparative genomic hybridization analysis identified genomic imbalances in 86% of MCLeu with a similar pattern than in MCL: gains of 3q, 8q involving MYC gene and 15q, and losses of 6q, 9p, 13q and 17p affecting P53 gene. Differently from MCL and CLL, genomic loss of 8p was frequently detected in MCLeu (83%). Although clinical presentation of MCLeu was indistinguishable from CLL, all patients but one had disease progression within three years. According to the immunologic and genomic profiles, two distinct subgroups of MCLeu were defined: one related to PLL, showing CD38-, deletion of P53, and MYC amplification and another which corresponds to a leukemic form of classical MCL, presenting with CD38+ and normal P53 and MYC status. MCLeu and MCL are closely related disorders, as they show similar genomic and molecular patterns. However, the deletion of the short arm of chromosome 8 may represent a specific marker for MCLeu. Two distinct subgroups of MCLeu may also be distinguished according to the immunologic and genomic cell profiles.

Expression of Cell Cycle Regulating Proteins in an Unusual Transformation of Mantle Cell Lymphoma

We describe here two patients with mantle cell lymphoma (MCL) who after a few years, developed to the diffuse large cell lymphoma (DLCL)(anaplastic centrocytic lymphoma) growing in a diffuse sheets without the classical MCL component. In both the initial and second biopsy specimens, in each case, tumor cells were positive for cyclin D1, sIgM, sIgD, and CD5, but were negative for CDlO and CD23. In a study of immunoglobulin heavy chain (IgH) gene rearrangement, using the polymerase chain reaction (PCR) method, the products obtained from each paired biopsy tissue sample were the same size, and in one case had an identical sequence to the non-mutated VH gene.Immunohistochemistry was used to examine the expression of p53, p27kipl and cyclin E. Interestingly, there was clear overexpression of p53 protein in case 1 but not in case 2, compared with other typical MCL cases. The expression of p27kipi in the second biopsies of each case was decreased compared with those in the initial biopsies. In case 2, however, p27kipi was clearly expressed in the first and second biopsies, in contrast to other typical MCL cases.Thus these 2 cases demonstrate not only that the variant form of MCL may arise de novo, but also that MCL may transform to DLCL at the time of relapse. Although the mechanism of tumor rogressiodtransforrnation is still poorly understood, the overexpression of p53 or p27kipi may be linked to a cellular mechanism involved in the development of the variant form of MCL.