Use of fludarabine in the treatment of mantle cell lymphoma, Waldenström's macroglobulinemia and other uncommon B- and T-cell lymphoid malignancies

2004 ◽  
Vol 5 ◽  
pp. S50-S61 ◽  
Author(s):  
Stephen A Johnson
Keyword(s):  
T Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Waldenström’S Macroglobulinemia ◽  
Lymphoid Malignancies ◽  
Mantle Cell ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Multicenter Phase II Study of Fludarabine Phosphate for Patients With Newly Diagnosed Lymphoplasmacytoid Lymphoma, Waldenström's Macroglobulinemia, and Mantle-Cell Lymphoma

1999 ◽  
Vol 17 (2) ◽  
pp. 546-546 ◽  
Author(s):  
James M. Foran ◽  
Ama Z.S. Rohatiner ◽  
Bertr Coiffier ◽  
Tiziano Barbui ◽  
Stephen A. Johnson ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Newly Diagnosed ◽  
Waldenström’S Macroglobulinemia ◽  
Fludarabine Phosphate ◽  
Mantle Cell ◽  
Duration Of Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

PURPOSE: Fludarabine phosphate (F-AMP) has significant activity in follicular lymphoma and in B-cell chronic lymphatic leukemia, where it has demonstrated high complete response (CR) rates. Lymphoplasmacytoid (LPC) lymphoma, Waldenström's macroglobulinemia (WM), and mantle-cell lymphoma (MCL) also present with advanced-stage disease and are incurable with standard alkylator-based chemotherapy. A phase II trial was undertaken to determine the activity of F-AMP in patients newly diagnosed with these diseases. PATIENTS AND METHODS: Between 1992 and 1996, 78 patients (aged 18 to 75 years) received intravenous F-AMP (25 mg/m2/d for 5 days, every 4 weeks) until maximum response, plus two further cycles as consolidation. The primary end point was response rate; secondary end points included time to progression (TTP), duration of response, and overall survival (OS). RESULTS: Forty-four (62%) of 71 assessable patients had a response to F-AMP (LPC lymphoma, 63%; WM, 79%; MCL, 41%); the CR rate was 15%. At a median follow-up of 1.5 years, 19 of 44 responding patients have had progression of lymphoma; the median duration of response was 2.5 years. The median survival has not yet been reached. There was no significant difference in the duration of response or OS between patients with different histologies; TTP was shorter in patients with MCL (P = .015). Myelosuppression was relatively common, and the treatment-related mortality (TRM) was 5%, mostly associated with pancytopenia and infection. CONCLUSION: Single-agent fludarabine phosphate is active in previously untreated LPC lymphoma and WM, with only moderate activity in MCL. However, the CR rate is low, and the TRM is relatively high. Its role in combination chemotherapy remains to be demonstrated.

Incidence of Transformation to Large Cell Lymphoma and to Second Malignancies in Symptomatic Patients with Waldenstrom’s Macroglobulinemia (WM) Treated with Cladribine (2-CdA) Combination Induction Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3065-3065 ◽  
Author(s):  
Ronjay Rakkhit ◽  
Kay B Delasalle ◽  
Maria B. Gavino ◽  
Sheeba K. Thomas ◽  
Meletios A Dimopoulos ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Large Cell ◽  
Nucleoside Analogues ◽  
Second Malignancy ◽  
Second Malignancies ◽  
Waldenström’S Macroglobulinemia ◽  
Waldenstrom's Macroglobulinemia ◽  
Large Cell Lymphoma ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Waldenstrom’s macroglobulinemia (WM) is an incurable malignancy characterized by malignant proliferation of lymphoplasmacytoid cells that produce a monoclonal IgM. Treatment of this disorder with nucleoside analogues like 2-CdA and fludarabine have resulted in excellent response rates and subsequent median survivals of approximately 8–9 years for previously untreated patients at our center. We, and others, have previously questioned the impact of initial treatment of Waldenstrom’s Macroglobulinemia on the risk of development of second malignancy and transformation (TR) to aggressive NHL (Non-Hodgkin’s Lymphoma). The objective of this analysis was to determine the incidence of transformation to large cell lymphoma and second malignancies in patients (pts) treated with 2-CdA either alone or in combination for induction therapy of patients with symptomatic WM. We performed a retrospective analysis of 111 consecutive, previously untreated patients with symptomatic WM who were treated with using 2 consecutive 4–6-week courses of either 2-CdA alone or in combination with other agents including prednisone (pred), cyclophosphamide (Cy), and rituximab (Rit) between January 1991 – July 2005. Patients received either 2-CdA 0.1 mg/kg by continuous infusion (CI) over 24 hours (hrs) × 7 days (n=16), an identical program with prednisone 60 mg/m2/d po for 7 days (n=22), 2-CdA 1.5 mg/m2 by subcutaneous injection (SC) q8 hrs × 7d + Cy 40 mg/m2 p.o. b.i.d. × 7d (n= 38), or identical 2-CdA (SC) + Cy + Rit 375 mg/m2 by intravenous infusion (IV) weekly × 4 weeks (n=35). Among 111 pts, 23 (21%) had either transformation to large cell lymphoma or development of a second malignancy within a median of 55 months. Ten patients (9%) had transformation to large cell lymphoma after treatment with 2-CdA alone (3 pts), 2-CdA/pred (1 pts), 2-CdA/Cy (3 pts) and 2CdA/Cy/Rit(3 pts). The median time to development of transformation to large cell lymphoma was 37 months (1mo – 110 mo) and 4 pts had transformation of disease within 13 months. An additional 13 pts (12%) developed other second malignancies including breast cancer (ca) (2pts), renal cell ca (2 pts), Basal cell ca of skin (2 pts), Hodgkin’s lymphomas (2 pts), cervical ca (1 pt), ovarian ca (1 pt), colorectal ca (1 pt), mesothelioma (1 pt), head/neck squamous cell ca (1 pt), vascular sarcoma (1 pt), bladder ca (1 pt) and prostate ca (1 pt), AML (1 pt) after treatment with 2-CdA (5 pts), 2-CdA/pred (1 pt), 2-CdA/Cy (4 pts), and 2CdA/Cy/Rit (3 pts). The median time to development of a second malignancy was 85.5 months and there did not appear to be any significant trend towards development of any particular secondary malignancy. While 2-CdA based induction regimens for WM provide excellent cause-specific survival for WM, this analysis suggests that the incidence of large cell transformation and second malignancies is pronounced among this group of patients with Waldenstrom’s Macroglobulinemia. Whether this rate of transformation/second malignancy is related to treatment with nucleoside analogues, or due to the natural progression of disease in patients with long survival after treatment with 2-CdA regimens remains unclear. We are currently extending the retrospective analysis to include a similar historic cohort of patients treated with alkylating agents and will provide updated data regarding both groups of patients at the time of presentation.

scholarly journals HSV-1 Encephalitis in an Elderly Man Receiving Ibrutinib for Waldenstrom’s Macroglobulinemia

2020 ◽  
Vol 2020 ◽  
pp. 1-2
Author(s):  
Mark R. Wallace
Keyword(s):  
Fungal Infections ◽  
Major Complication ◽  
Hepatitis E ◽  
Lymphocytic Leukemia ◽  
Waldenström’S Macroglobulinemia ◽  
Herpes Encephalitis ◽  
Mantle Cell ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Ibrutinib is a major new addition to the therapeutic armamentarium for chronic lymphocytic leukemia, mantle cell lymphoma, Waldenstrom’s macroglobulinemia, and chronic graft versus host disease. Though ibrutinib has proven to be a revolutionary new small molecule agent, and has relatively minimal toxicity as compared to traditional chemotherapy, infections have emerged as a major complication of therapy. While fungal infections have been the most problematic (including CNS aspergillosis), zoster, hepatitis B reactivation, and chronic hepatitis E have been reported in association with ibrutinib therapy. This report describes a case of herpes encephalitis in an 86-year-old Waldenstrom’s patient receiving ibrutinib and speculates as to whether this late life encephalitis may have been related to ibrutinib.

A Phase I Study of Vorinostat (V) in Combination with Rituximab (R), Ifosphamide, Carboplatin, and Etoposide (ICE) for Patients with Relapsed or Refractory Lymphoid Malignancies or Untreated T- or Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3696-3696 ◽  
Author(s):  
Lihua E. Budde ◽  
Michelle M. Zhang ◽  
Andrei R. Shustov ◽  
John M. Pagel ◽  
Thomas A. Warr ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoid Malignancies ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 3696 Poster Board III-632 Platinum based regimens such as ICE with or without Rituximab (RICE) have been widely used to treat relapsed or refractory lymphoid malignancies prior to transplantation. However, a significant portion of patients do not respond to treatment, and improved therapies are needed. Vorinostat (V) is an oral HDAC inhibitor with moderate toxicity and has clinical activity against a variety of tumors including cutaneous T cell lymphoma. Preclinical data demonstrated marked anti-tumor synergism between V and platinum analogues as well as etoposide. We present data from a phase I, open-label, multicenter, dose escalation study estimating the maximally tolerated dose of V that can be combined with RICE or ICE (V-RICE or VICE) in patients with relapsed or refractory lymphoid malignancies or untreated T- or Mantle Cell Lymphoma. Other endpoints include tolerability, exploratory anti-tumor activity and impact of above regimen on stem cell reserve. Patients (aged ≥18 years, an ECOG performance status of 0-2, measurable disease, no active central nervous system involvement, adequate bone marrow, hepatic and renal function, no active arrhythmias on EKG) were sequentially enrolled on escalating doses of V combination therapy using the “two stage” design introduced by Storer with single patient cohorts until a dose limiting toxicity (DLT) is observed, followed by cohorts of 4 patients. A DLT was defined as any gastrointestinal grade 3 NCI-CTCAE adverse event (AE) lasting longer than 7 days, or any related non-hematologic grade 4 or 5 AE; any event that prevents the completion of one full cycle of therapy (5 days of V) due to toxicity from V; or any AE at the discretion of the principal investigator. Therapy consisted of V ranging from 400 mg daily to 700 mg BID days 1 to 5 in combination with standard RICE or ICE on days 3 to 5 every 21 days. A total of 18 patients have been enrolled on this study thus far (9 in stage 1, 9 in stage 2) and 14are fully evaluable to date, including: Hodgkin lymphoma (4), T-cell lymphoma (3); mantle cell lymphoma (2); diffuse large B cell lymphoma (2); follicular lymphoma (2), and chronic lymphocytic leukemia (1). Baseline characteristics (n=14) included: median age 55 (range: 33-67), male 10 (71%), stage III/IV 14 (100%), median number of prior therapies 2 (range: 0-6), elevated LDH 5 (35%), prior anthracycline 13 (93%), prior platinum 2 (14%), refractory diseases 5 (36%), relapsed diseases 8 (57%), untreated disease 1 (7%). A maximum V dose of 700 mg BID was attained in stage I (Table). The dose adjustment schema of stage II has ranged from 600 mg BID to 400 mg BID currently. Among the 14 evaluable patients, six received only1 cycle of treatment (3/5 patients declined the second cycle; 2/5 patients developed DLT), 8 completed 2 cycles. Eight of 14 (57%) patients experienced non-hematologic AEs≥ grade 3 with most common being nausea, vomiting, or diarrhea seen in 6 and grade 4 hypokalemia in 2. Twelve patients (86%) responded including 1 with complete remission (CR), 2 with unconfirmed CR, and 9 with partial responses. One patient had stable disease and one had disease progression. Nine of 12 patients (75%) who attempted peripheral blood stem cell collection following VICE/V-RICE were successful (>5×106 CD34+/kg) Collectively, these findings indicate that the combination of vorinostat with RICE or ICE, is feasible and active in patients with lymphoid malignancies. Special attention should be given to the management of the frequent gastrointestinal AEs. Pending identification of the MTD, phase II evaluation of VICE or V-RICE regimen will be designed to formally define its efficacy. Table Summary of DLTs and responses at various dose levels Stage Dose level Dose n DLTs responses I 1 400 mg QD 2 0 PR(1); SD (1) 2 300 mg BID 1 0 PR (1) 3 400 mg BID 1 0 PD (1) 4 500 mg BID 2 0 PR (1); CR (1) 5 600 mg BID 1 0 PR (1) 6 700 mg BID 2 1 PR (2) II 5 600 mg BID 4 3 PR (1); CRu (3) 4 500 mg BID 1 1 PR (1) Total - - 14 5 12 (86%) Disclosures: No relevant conflicts of interest to declare.

Comprehensive Assessment of Cytokines and Chemokines In Patients with Waldenstrom's Macroglobulinemia Reveals a Distinct Profile with Pathobiological and Clinical Relevance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1911-1911
Author(s):  
Megan Lewicki ◽  
Bryan Ciccarelli ◽  
Zachary Hunter ◽  
Philip Brodsky ◽  
Robert Manning ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Regulation ◽  
Waldenström’S Macroglobulinemia ◽  
Gm Csf ◽  
Cytokines And Chemokines ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 1911 Waldenstrom's macroglobulinemia (WM) is a B-cell lymphoplasmacytic disorder characterized by elevated clonal IgM secretion and bone marrow infiltration. Dysregulation of plasma cytokines and chemokines have been described in related malignancies, though large scale comparative efforts to WM have been limited. We therefore evaluated the levels of 20 cytokines, 27 chemokines, and soluble CD27 (sCD27) given the putative memory B-cell origin of WM in peripheral blood derived plasma obtained from 54 patients with WM, 31 patients with Multiple Myeloma (MM), and 37 patients with monoclonal gammopathy of unknown significance (MGUS) using the Bio-Plex Pro Human Cytokine 27-plex Assay and the Bender instant soluble CD27 ELISA. Twenty-six age-matched normal donors (ND) were used as controls. Among WM patients, we detected significantly higher levels of the cytokines IL-1Rα (p<0.001), IL-5 (p=0.009), IL-6 (p=0.017), IL-8 (p<0.001), IL-10 (p<0.001), IL-17 (p<0.001), INFg (p=0.022) and GM-CSF (p<0.001), as well as the chemokines CCL2 (p<0.001), CCL3 (p<0.001), and CXCL8 (p<0.001). IL-2 (p<0.001), IL-9 (p< 0.001), IL-15 (p < 0.001), FGF2 (p<0.001), and sCD27 (p<0.001) levels were also significantly increased, while IL-7 levels were decreased (p<0.001). The same pattern of up and down-regulation was also detected in MM and MGUS, suggesting these diseases share some pathophysiological characteristics. In distinction, we observed decreased levels of CCL11 (p<0.02) and RANTES <0.02) only among WM patients in comparison to MM, MGUS, and NDs. Taken together, these data highlight similarities and differences in cytokine and chemokine profile for WM patients, which may be relevant to WM pathogenesis (Figure 1). In addition, sCD27 was associated with several clinical markers, notably correlating negatively with B2M (rho = -0.42, p = 0.016) and positively with CD8+ T-cell percentage (rho = 0.44, p < 0.001). sCD27 was also increased 1.9 fold in WM patients with a familial history of psoriasis (p = 0.021, n = 6). Among the cytokines and chemokines, GM-CSF was decreased 1.7 fold in the presence of lymphadenopathy (p = 0.003, n = 15), and IL-7 and CXCL10 were both increased in the four previously treated patients (fold = 5.5, p = 0.005; fold = 3.4, p = 0.003). In conclusion, there is significant cytokine, chemokine, and soluble CD27 dysregulation in WM, MM, and MGUS corresponding to important clinical correlations in WM. In addition to B-cell regulation, several of these dysregulations are also involved in T-cell regulation, signifying a need for further understanding of T-cell involvement in WM. These data demonstrate that further investigation of cytokine involvement in the pathogenesis and prognosis of these diseases is warranted. Disclosures: No relevant conflicts of interest to declare.

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