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Yazeed Sawalha, David A Bond, Lapo Alinari Department of Internal Medicine, Division of Hematology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USACorrespondence: Yazeed SawalhaDepartment of Internal Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital, A350B Starling-Loving Hall, 320 W. 10th Ave., Columbus, OH 43210, USATel +1 614-293-0837Fax +1 614-293-7526Email Yazeed.Sawalha@osumc.eduAbstract: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma characterized by an aggressive clinical course in the majority of patients. Despite recent improvements in outcomes, MCL remains incurable and a major therapeutic challenge. BTK inhibitors are the preferred treatment option for patients with relapsed/refractory MCL, including those unfit for chemotherapy or those with chemoresistant disease. In addition to ibrutinib and acalabrutinib, the FDA recently approved zanubrutinib for the treatment of patients with relapsed/refractory MCL based on the results of two Phase 2 clinical trials showing overall response rates of 85– 87% with complete responses in 30– 77% of patients. Compared with ibrutinib, zanubrutinib is more selective for BTK and has less off-target inhibition, which is thought to limit certain toxicities although direct comparative data are still lacking. This review article summarizes data from clinical trials of currently FDA-approved BTK inhibitors in MCL with a focus on zanubrutinib.Keywords: BTK, zanubrutinib, ibrutinib, acalabrutinib

Purpose Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. Patients and Methods The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification. Results Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). Conclusion Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

BACKGROUND AND OBJECTIVES: This multinational retrospective study compares the outcomes of patients with primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis after first-generation (dose-intensive regimens), third-generation (alternating regimens) and high-dose chemotherapy strategies, frequently with adjuvant radiation therapy. DESIGN AND METHODS: Between August 1981 and December 1999, a total of 426 previously untreated patients with confirmed diagnosis were enrolled in 20 institutions to receive combination chemotherapy with either first generation (CHOP or CHOP-like) regimens, third generation (MACOP-B, VACOP-B, ProMACE CytaBOM) regimens or high-dose chemotherapy (HDS/ABMT). RESULTS: With chemotherapy, complete response (CR) rates were 49% (50/105), 51% (142/277) and 53% (23/44) with first generation, third generation and high-dose chemotherapy strategies, respectively; partial response (PR) rates were 32%, 36% and 35%, respectively. All patients who achieved CR and 124/142 (84%) with PR had radiation therapy on the mediastinum. The final CR rates became 61% for CHOP/CHOP-like regimens, 79% for MACOP-B and other regimens, and 75% for HDS/ABMT. After median follow-ups from attaining CR of 48.5 months for CHOP/CHOP-like regimens, 51.7 months for MACOP-B type regimens and 32.4 months for HDS/ABMT, relapses occurred in 15/64 (23%), 27/218 (12%) and 0/33 (0%) patients, respectively. Projected 10-year progression-free survival rates were 35%, 67% and 78%, respectively (p=0.0000). Projected 10-year overall survival rates were 44%, 71% and 77%, respectively (p=0.0000), after median follow-ups from diagnosis of 52.3 months, 54.9 months and 35.8 months, respectively. INTERPRETATION AND CONCLUSIONS: In patients with PMLBCL with sclerosis, MACOP-B plus radiation therapy may be a better strategy than other treatments; these retrospective data need to be confirmed by prospective studies. The encouraging survival results after high dose chemotherapy require confirmation in selected high-risk patients.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of pegfilgrastim, in combination with salvage chemotherapy, in mobilizing CD34(+) stem cells into the peripheral blood of pretreated lymphoma patients. DESIGN AND METHODS: This was an open-label phase II study including 25 pretreated patients (Hodgkin's disease=4; aggressive non-Hodgkin's lymphoma=21). The primary end-point of the study was the successful mobilization of a target cell dose of 2x10(6) CD34(+) cells/kg in lymphoma patients receiving ifosfamide, epirubicin and etoposide (IEV) chemotherapy and a fixed dose (6 mg) of pegfilgrastim given as single subcutaneous injection. RESULTS: Following chemotherapy, all patients had grade 4 neutropenia that lasted a median of 1.5 days (1-3). Pegfilgrastim treatment was well tolerated and only 2/25 patients required pain-control medication. CD34+ cells were mobilized in all patients. The median (range) peak value of peripheral blood CD34+ cells after IEV chemotherapy and pegfilgrastim was 141x10(6)/L (12.8-386) and occurred almost invariably on day +14 (13-16). Twenty-three of the 25 patients underwent a single standard volume leukapheresis to collect a median of 8.7x10(6) CD34(+) cells/kg (1.78-17.3). Twenty four/25 patients (96%) reached the target cell dose of 2x10(6) CD34(+) cells/kg. High concentrations of circulating CD34+ cells (> 50x10(6)/L) were observed for several days after the achievement of the peak value. All the study patients were transplanted with their pegfilgrastim-mobilized CD34(+) cells and showed a rapid and sustained engraftment after high-dose chemotherapy. INTERPRETATION AND CONCLUSIONS: Our results show that pegfilgrastim as an adjunct to chemotherapy is a predictable and highly effective mobilization regimen in pretreated lymphoma patients.

In this work we examine the characteristics and outcome of patients with Hodgkin's disease (HD) treated with high-dose therapy (HDT) and autologous transplantation at our Institute between 1982 to 2000.A retrospective analysis was performed examining patients' characteristics, prior chemotherapy regimens, pre-transplant disease status, HDT regimen, source of stem cells, time for hematopoietic recovery, complications of transplantation, response rates, overall survival (OS) and relapse-free survival (RFS).Ninety-seven patients with HD were treated and had estimated 10-year OS and RFS rates of 32% and 60%, respectively. Disease status (sensitive vs. refractory) before HDT was the most powerful predictive parameter for OS and RFS in both univariate and multivariate analyses. The rate of transplant-related mortality in the whole cohort was only 1% whereas the rate of second malignancies was 3%.Our results confirm that HDT with autologous transplantation is associated with a durable RFS in a remarkable proportion of HD patients and that the procedure has a very low global early and late toxicity.

A retrospective analysis was performed to assess the efficacy of various treatments of non-Hodgkin's primary bone lymphomas (PBL).Fifty-two consecutive, previously untreated PBL patients were seen between the years 1982 and 1998. Information was obtained regarding each patient's presentation and clinical course. Histology was reviewed in all cases. Modern immunohistochemical stains were performed on each case.Regarding therapeutic approach, we observed a complete response (CR) in 35/41 (85%) patients treated with chemotherapy with/without radiation therapy and in 7/11 (64%) patients who received radiation therapy alone. Relapses were observed in only 2/35 (6%) patients after chemotherapy (with/without radiation therapy), as compared with 4/7 (57%) patients after radiation therapy alone (p = 0.004); the relapse-free survival curves of these two subsets were significantly different. At both univariate and multivariate analysis only type of front-line therapeutic approach (chemotherapy with/without radiation therapy vs. radiation therapy alone) turned out to have a significant prognostic influence.Our data indicate that in PBL use of chemotherapy or combined-modality therapy seems to provide more durable CRs than radiation therapy alone.