Ibrutinib-induced acute kidney injury via interstitial nephritis.

The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 µmol/L to 125 µmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.

How I treat prolymphocytic leukemia.

T- and B-cell subtypes of prolymphocytic leukemia (PLL) are rare, aggressive lymphoid malignancies with characteristic morphologic, immunophenotypic, cytogenetic, and molecular features. Recent studies have highlighted the role of specific oncogenes, such as TCL-1, MTCP-1, and ATM in the case of T-cell and TP53 mutations in the case of B-cell prolymphocytic leukemia. Despite the advances in the understanding of the biology of these conditions, the prognosis for these patients remains poor with short survival and no curative therapy. The advent of monoclonal antibodies has improved treatment options. Currently, the best treatment for T-PLL is intravenous alemtuzumab, which has resulted in very high response rates of more than 90% when given as first-line treatment and a significant improvement in survival. Consolidation of remissions with autologous or allogeneic stem cell transplantation further prolongs survival, and the latter may offer potential cure. In B-PLL, rituximab-based combination chemo-immunotherapy is effective in fitter patients. TP53 abnormalities are common and, as for chronic lymphocytic leukemia, these patients should be managed using an alemtuzumab-based therapy. The role of allogeneic transplant with nonmyeloablative conditioning needs to be explored further in both T- and B-cell PLL to broaden the patient eligibility for what may be a curative treatment.

[Impending liver failure after chemoimmunotherapy-induced reactivation of hepatitis B - successful treatment with entecavir]. / Drohendes Leberversagen nach Chemoimmuntherapie-induzierter Reaktivierung einer Hepatitis B - erfolgreiche Therapie mit Entecavir.

HISTORY AND CLINICAL FINDINGS: An 83-year old woman had been treated with bendamustin and rituximab for prolymphocytic leukemia. Two weeks after cycle 6 of chemotherapy, signs and symptoms of a severe hepatitis occurred. INVESTIGATIONS: Highly elevated values for AST (1353 U/l) and bilirubin (27.8 mg/dl), impaired coagulation parameters (INR 1,68) and the detection of ascites led to the diagnosis of an impending liver failure induced by reactivation of a hitherto unknown hepatitis B (HBs antigen pos., HBe antigen pos., anti HBc IgG pos., HBV DNA 1,65 Mio copies/ml). TREATMENT AND COURSE: After an immediately started treatment with entecavir (0.5 mg/d po), symptoms and laboratory parameters rapidly improved. 4 months later liver chemistry was completely normal and HBV DNA was negative. After 8 months, a seroconversion to anti HBs was noted. CONCLUSION: In single cases, life threatening complications of chemotherapy induced reactivation of hepatitis B may be successfully treated by potent and stabile nucleosidanalogs.

Clinical efficacy of immunochemotherapy with fludarabine, epirubicin and rituximab in the treatment for chronic lymphocytic leukaemia and prolymphocytic leukaemia.

Despite some considerable progress in the therapy for chronic lymphocytic leukaemia (CLL) owing to fludarabine-based regimens and rituximab, no curative treatment is available so far. We conducted an explorative phase II study in patients with CLL, prolymphocytic leukaemia (PLL) and leukaemic lymphoplasmacytic lymphoma (LL) with the combination of fludarabine, epirubicin and rituximab (FER) to improve the complete remission (CR) rate and progression-free survival (PFS). Fludarabine 25 mg/m(2) was administered i.v. on days 1-5 and epirubicin 25 mg/m(2) i.v. on days 4 and 5, and rituximab was added at a dose of 375 mg/m(2) i.v. day 1 in the first cycle and at a dose of 500 mg/m(2) in all consecutive cycles. Patients exhibiting responsive disease after FER were eligible to receive maintenance therapy of up to 12 cycles of rituximab 375 mg/m(2) bimonthly. Forty-four patients (38 CLL, 4 PLL and 2 LL) with a median age of 65 yrs (43-84 yrs) were evaluable. Seventeen patients with CLL had stage Binet C, 14 Binet B and seven symptomatic or rapid progressive stage Binet A. Cytogenetic features showed normal karyotype in nine cases, an isolated deletion (del) 13q in 12 patients, trisomy 12 in 7, del 11 in two and del 17p in 4. Half of the patients (48%) had mutated IgVH genes. Treatment with FER achieved an overall response rate of 95%, including 63% CRs and 32% PRs. Haematological toxicity was considerable. After a median follow-up period of 34 months (range: 8-84 months), median PFS was 61 months and overall survival was yet not reached. All patients with PLL and LL achieved CR. The data support the high efficacy of the combination of rituximab with chemotherapy (FE) and are suggestive of possible benefit with rituximab maintenance therapy for PFS and DFS.

Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy.

The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit "oncogene-addicted" growth, while they do display "cytokine-addicted" proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 hrs. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G(1) block, while paclitaxel triggered a G(2)/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not "oncogene-addicted" may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors.

Cryptococcal immune reconstitution inflammatory syndrome following alemtuzumab therapy.

Alemtuzumab is a lymphocyte ablative agent that may cause susceptibility to severe opportunistic infections similar to those seen in AIDS. Pathogen-specific immune reconstitution syndromes can complicate antiretroviral therapy and immune recovery in HIV-infected patients. We present the first reported case of immune reconstitution syndrome associated with T lymphocyte recovery after alemtuzumab therapy.

Current treatment options in prolymphocytic leukemia.

Prolymphocytic leukemia (PLL) is a rare lymphoproliferative disorder characterized by marked leukocytosis and splenomegaly. PLL accounts for approximately 2% of chronic lymphoid leukemias. The clinical course is progressive in the majority of cases due to the resistance of the disease to conventional chemotherapy. The disease is divided according to the cell of origin into the B- (B-PLL) and T-cell (T-PLL) types. T-PLL and B-PLL are morphologically identical, but lymphadenopathy and skin involvement are more common in T-PLL than in B-PLL. Approximately 80% of cases are of B-cell phenotype. T-PLL has a more aggressive course, poorer response to chemotherapy, and shorter median survival than B-PLL. PLL has poorer prognosis than chronic lymphocytic leukemia (CLL), and the patients with static disease for a longer period of time are rare. In general, B-PLL patients have better prognosis than T-PLL patients. PLL is still considered an incurable disease. Similarly to CLL, treatment is not indicated in asymptomatic patients. In previous decades, splenectomy, splenic irradiation, leucapheresis, and alkylating agents used alone or in combination with other cytotoxic agents have been used for the treatment of PLL. Subsequently, purine nucleoside analogs (fludarabine, cladribine, and pentostatin) have been introduced for the therapy of these disorders. More recently, monoclonal antibodies, especially alemtuzumab, have been found more effective, especially in T-PLL. Finally, high-dose chemotherapy followed by allogenic or autologous stem cell transplantation seems to be an effective, probably curative, strategy for the treatment of selected patients with PLL. In this review, current therapeutic strategies in PLL are presented.

Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies.

PURPOSE: Everolimus (RAD001, Novartis), an oral derivative of rapamycin, inhibits the mammalian target of rapamycin (mTOR), which regulates many aspects of cell growth and division. A phase I/II study was done to determine safety and efficacy of everolimus in patients with relapsed or refractory hematologic malignancies. EXPERIMENTAL DESIGN: Two dose levels (5 and 10 mg orally once daily continuously) were evaluated in the phase I portion of this study to determine the maximum tolerated dose of everolimus to be used in the phase II study. RESULTS: Twenty-seven patients (9 acute myelogenous leukemia, 5 myelodysplastic syndrome, 6 B-chronic lymphocytic leukemia, 4 mantle cell lymphoma, 1 myelofibrosis, 1 natural killer cell/T-cell leukemia, and 1 T-cell prolymphocytic leukemia) received everolimus. No dose-limiting toxicities were observed. Grade 3 potentially drug-related toxicities included hyperglycemia (22%), hypophosphatemia (7%), fatigue (7%), anorexia (4%), and diarrhea (4%). One patient developed a cutaneous leukocytoclastic vasculitis requiring a skin graft. One patient with refractory anemia with excess blasts achieved a major platelet response of over 3-month duration. A second patient with refractory anemia with excess blasts showed a minor platelet response of 25-day duration. Phosphorylation of downstream targets of mTOR, eukaryotic initiation factor 4E-binding protein 1, and/or, p70 S6 kinase, was inhibited in six of nine patient samples, including those from the patient with a major platelet response. CONCLUSIONS: Everolimus is well tolerated at a daily dose of 10 mg daily and may have activity in patients with myelodysplastic syndrome. Studies of everolimus in combination with therapeutic agents directed against other components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway are warranted.

Prolymphocytic leukemias.

T and B subtypes of prolymphocytic leukemias (PLLs) are rare, highly aggressive lymphoid malignancies with characteristic morphologic, immunophenotypical, cytogenetic, and molecular features. Recent studies have highlighted the role of specific oncogenes such as TCL1, MTCP-1, and ATM in the case of T-cell and p53 mutations in the case of B-cell PLLs. Despite the advances in the understanding of the biology of these conditions, prognosis for these patients remains poor with short survival and no curative treatment. The advent of monoclonal antibody therapy has improved treatment options for this group. In particular, the use of Campath-1H, in T-PLL has more than doubled median survival. The role of allogeneic transplant with nonmyeloablative conditioning needs to be explored further.

T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive post-thymic malignancy with poor response to conventional treatment and short survival. It can readily be distinguished from other T-cell leukemias on the basis of the distinctive morphology, immunophenotype, and cytogenetics. Consistent chromosomal translocations involving the T-cell receptor gene and one of two protooncogenes (TCL-1 and MTCP-1) are seen in the majority of cases and are likely to be involved in the pathogenesis of the disorder. The CD52 antigen is expressed at high density on the malignant T-cells and therapy with alemtuzumab, a humanized IgG1 antibody that targets this antigen, has produced promising results. In relapsed/refractory patients overall and complete response rates have been seen in up to 76% and 60%, respectively. In previously untreated patients, complete remission rates of 100% have been reported. These responses are durable and translate into improved survival for responders. However, relapse is inevitable and strategies using both autologous and allogeneic stem cell transplantation are currently being explored. Additional clinical trials are investigating the use of alemtuzumabin combinations with chemotherapy, either concurrent or sequential. In the future we hope to have a betterunderstanding of how best to integrate these therapeutic approaches to further prolong survival for patients with T-PLL.

Pentostatin and purine analogs for indolent lymphoid malignancies.

Pentostatin has been shown to be active in a variety of B- and T-cell malignancies. The drug is a tight inhibitor of adenosine deaminase, a key degradative enzyme of purine metabolism present in all human tissues, with the highest levels found in the lymphoid system. Early clinical trials indicated that this agent was highly active in acute lymphoblastic leukemias with high intracellular adenosine deaminase levels. Relatively high doses of the drug were needed, which was associated with severe adverse events. Through the efforts of a few investigators, better tolerated, low-dose regimens have been shown to be extremely active in lymphoproliferative diseases with very low intracellular adenosine deaminase levels such as hairy cell leukemia, B- and T-cell chronic leukemias, T-cell cutaneous lymphomas and low-grade non-Hodgkin lymphomas. Clinical as well as experimental data have indicated that this drug induces lymphocyte-specific cytotoxicity, and myelosuppressive adverse events have been minimal. Although all the purine analogs have shown similar activity, the advantage of pentostatin is the relatively specific cytotoxicity against lymphocytes, which permits treatment even in patients with severe cytopenias. Although no direct comparisons of the purine analogs have been performed, pentostatin may be preferred due to this property.

T-cell prolymphocytic leukemia: a single-institution experience.

BACKGROUND: T-cell prolymphocytic leukemia is an uncommon, aggressive, mature T-cell leukemia characterized by proliferation of T-cell lymphocytes. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of this disorder from its B-cell counterpart and other mature T-cell leukemias. PATIENTS AND METHODS: The clinical, pathologic, and cytogenetic features of 57 patients with T-PLL who were evaluated at the Department of Leukemia, M. D. Anderson Cancer Center (MDACC) from 1986 to 2004 were examined. RESULTS: The most common cytogenetic abnormality was inv(14)(q11;q32), which was present in 7 patients. In all 7 patients, this abnormality was associated with other chromosomal aberrations. Patients treated with alemtuzumab at MDACC had a significantly better response rate (P = 0.02) and survival rate (P = 0.002). There were no significant differences in survival based on Tcl-1 expression or different patterns of CD4 and CD8 expression. CONCLUSION: Treatment with alemtuzumab results in higher response rates and a better survival rate in patients with T-cell prolymphocytic leukemia.

Mature T-cell leukemias.

Mature T-cell and NK-cell leukemias are a group of relatively uncommon neoplasms derived from mature or postthymic T-cells accounting for a relatively small percentage of lymphoid malignancies. The recent availability of modern immunophenotypic and molecular tools has allowed a better distinction of these disorders from their B-cell counterparts. Similarly, identification of recurrent cytogenetic abnormalities, as well as plausible mechanisms through which these molecular events influence cellular signaling pathways, have created further insight into the pathogenesis of these disorders. Furthermore, the availability of new agents such as alemtuzumab has generated significant interest in devising specific therapeutic strategies for these malignancies. Herein, we review the clinical and pathological features of mature T-cell leukemias.