Safety and efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with relapsed or refractory follicular lymphoma (CITADEL-102): A phase 1 study.

Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit with monotherapy in a phase 2 study in relapsed or refractory (R/R) follicular lymphoma (FL). CITADEL-102 (NCT03039114), a phase 1, multicenter study, assessed the efficacy of parsaclisib in combination with obinutuzumab and bendamustine in patients with R/R FL. Patients were ≥18 years of age with histologically confirmed and documented CD20-positive FL, and R/R to previous rituximab-containing treatment regimens. Part one (safety run-in) determined the maximum tolerated dose of parsaclisib in combination with standard dosage regimens of obinutuzumab and bendamustine. Part two (dose expansion) was an open-label, single-group design evaluating safety, tolerability (primary endpoint), and efficacy (secondary endpoint) of parsaclisib combination therapy. Twenty-six patients were enrolled in CITADEL-102 and all patients received parsaclisib 20 mg once daily for 8 weeks, followed by 20 mg once weekly thereafter, in combination with obinutuzumab and bendamustine. One patient in safety run-in experienced a dose-limiting toxicity of grade 4 QT interval prolongation that was considered related to parsaclisib. Eight patients (30.8%) discontinued treatment due to treatment-emergent adverse events (TEAEs) of colitis (2 [7.7%]), alanine aminotransferase and aspartate aminotransferase increase (both in one patient [3.8%]), neutropenia, thrombocytopenia, QT prolongation, tonsil cancer, and maculopapular rash (each 1 [3.8%]). The most common reported TEAEs were pyrexia (53.8%), neutropenia (50.0%), and diarrhea (46.2%). Twenty-three patients (88.5%) experienced grade 3 or 4 TEAEs; the most common were neutropenia (34.6%), febrile neutropenia (23.1%), and thrombocytopenia (19.2%). Seventeen patients (65.4%) had a complete response and 3 patients (11.5%) had a partial response, for an objective response rate of 76.9%. Overall, results from CITADEL-102 suggest that the combination of parsaclisib with obinutuzumab and bendamustine did not result in unexpected safety events, with little evidence of synergistic toxicity, and demonstrated preliminary efficacy in patients with R/R FL who progressed following prior rituximab-containing regimens.

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma.

Acalabrutinib, a Bruton tyrosine kinase inhibitor, demonstrated greater selectivity and improved safety versus ibrutinib in a head-to-head trial in relapsed/refractory (R/R) chronic lymphocytic leukaemia. In the R/R marginal zone lymphoma (MZL) cohort (phase 2) of a phase 1b/2 trial (NCT02180711), 43 patients with MZL and at least one prior therapy received acalabrutinib 100 mg twice daily until disease progression or unacceptable toxicity [median age 69 years (range 42-84); median one (1-4) prior systemic regimens]. Median follow-up was 13.3 months (range 0.5-45.5). Among 40 patients evaluable for response, investigator-assessed overall response rate was 53% [95% confidence interval (CI) 36%-69%] with five (13%) complete responses. Tumour reduction occurred in 40 (93%) of the treated patients. Median time to response was 2.9 months (median duration of response not estimable). Estimated median progression-free survival (PFS) was 27.4 months (12-month PFS rate, 67%). Five patients died (disease progression, n = 4; septic shock, n = 1). Seventeen patients (40%) had grade 3 or higher adverse events (AEs), most commonly neutropenia (14%), anaemia, dyspnoea (7% each), fatigue and thrombocytopenia (5% each). Hypertension occurred in 5%; atrial fibrillation/flutter and major haemorrhage were not reported. AEs led to treatment discontinuation in three (7%) patients. Acalabrutinib was active and well tolerated in patients with R/R MZL.

Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia.

B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.

Carfilzomib and dexamethasone induction with lenalidomide, clarithromycin and dexamethasone consolidation and lenalidomide maintenance for newly diagnosed multiple myeloma.

Combination treatment regimens including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and a corticosteroid are standards of care for initial treatment of multiple myeloma (MM). We aimed to evaluate if a sequential treatment program using PI induction followed by IMiD based consolidation and maintenance could achieve similar outcomes with reduced toxicities. This phase 2 study was designed to assess the safety and efficacy of the Car-BiRd regimen: carfilzomib and dexamethasone (Kd) induction until maximum response, followed by lenalidomide, clarithromycin and dexamethasone (BiRd) consolidation until next maximum response, then lenalidomide maintenance in patients with newly diagnosed MM. Seventy-two patients, including both transplant eligible and ineligible patients, were enrolled and evaluated for response. The overall response rate to the Car-BiRd regimen was 94% with 83% of patients achieving a ≥ VGPR and 35% achieving a CR/sCR. The rate of CR/sCR increased from 7% with Kd induction to 21% with BiRd consolidation and 35% with lenalidomide maintenance. These results did not meet the study's target endpoint of a CR rate of 55%. The median PFS using this deferred transplant approach was 37.3 months (95% CI 27.9, 52.7) and median OS was not reached with a median follow-up of 60 months. Toxicities were primarily low grade and manageable. Hematologic toxicities were lower than those expected with a combination PI/IMiD protocol. The sequential Car-BiRd regimen is an effective and safe approach for the upfront treatment of MM including patients unfit for transplant.

Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma.

We report 5-year follow-up of a multicenter phase 2 study of lenalidomide plus rituximab (LR) as initial treatment of mantle cell lymphoma (MCL). The regimen includes induction and maintenance with the LR doublet. Treatment was continuous until progression, with optional discontinuation after 3 years. The median age of the 38 participants was 65 years, with MCL international prognostic index scores balanced among low, intermediate, and high risk (34%, 34%, and 32%, respectively). Twenty-seven (75%) of the 36 evaluable patients completed ≥3 years of study treatment. At a median follow-up of 64 months (range, 21-78), the 3-year progression-free survival (PFS) and overall survival (OS) were 80% and 90%, respectively, with 5-year estimated PFS and OS of 64% and 77%, respectively. During maintenance, hematologic adverse events (AEs) included asymptomatic grade 3 or 4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia) and mostly grade 1 or 2 infections managed in the outpatient setting (45% upper respiratory infection, 21% urinary tract infection, 13% sinusitis, 11% cellulitis, 8% pneumonia). Nonhematologic AEs, such as constitutional and inflammatory symptoms, occurred at reduced frequency and intensity compared with induction. A peripheral blood minimal residual disease (MRD) assay (clonoSEQ) showed MRD-negative complete remission in 8 of 10 subjects who had completed ≥3 years of treatment and with available samples for analysis. With longer follow-up, LR continues to demonstrate durable responses and manageable safety as initial induction and maintenance therapy for MCL (ClinicalTrials.gov NCT01472562).

Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma.

Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma.

Carfilzomib and dexamethasone (Kd) has significant activity in relapsed and refractory multiple myeloma. Kd has not previously been evaluated in newly diagnosed multiple myeloma (NDMM). We report a single-arm phase 2 study of 72 patients with NDMM to evaluate the efficacy and tolerability of Kd induction. Carfilzomib was administered in two dosing cohorts with dosing of 20/45 mg/m2 in the first 25 patients and 20/56 mg/m2 in the subsequent 47 patients. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle, dexamethasone 20 mg was administered orally on days 1, 2, 8, 9, 15, 16, 22 and 23. Treatment was continued to maximum response, progression of disease, or regimen intolerability. Endpoints included overall response rate (ORR), regimen toxicity and impact of carfilzomib on CD34+ stem cell collection yield. Sixty-five pts achieved at least a partial response (PR) for an ORR of 90%. The maximum response achieved was complete response or better in 5 (7%), very good partial response (VGPR) in 42 (58%), PR in 18 (25%) and stable disease in 7 pts (10%). Toxicities were predominantly low grade with 547 grade 1/2 adverse events and 44 grade ≥3 events. The rate of grade ≥3 cardiovascular adverse events was 11.1% with eight observed events. The activity of Kd described represents the highest rate of overall response and ≥VGPR for any 2-agent combination in NDMM reported to date. Kd demonstrated a safety profile consistent with previously reported carfilzomib studies.

Epidermotropic CXCR3 positive marginal zone lymphoma: a distinctive clinical histopathological entity potentially originating in the skin; it does not always indicate splenic marginal zone lymphoma.

Epidermotropic B cell lymphoma represents a rare form of marginal zone lymphoma presenting as a disseminated skin rash resembling pityriasis rosea. To date there are 8 reported cases. In addition to the widespread nature of the skin rash, there is a proclivity for spleen and bone marrow involvement raising consideration regarding its categorization as a systemic lymphoma. We present an 89-year-old man with epidermotropic B cell lymphoma, who presented with a pityriasis rosea-like skin rash. An initial diagnosis of diffuse large cell B cell lymphoma was made based on the extent of dermal-based large cell infiltration. However, after recognizing the epidermotropic component and the distinctive clinical presentation, a diagnosis of epidermotropic B cell lymphoma was rendered. There was minimal bone marrow involvement based only on flow cytometric analysis, but there was no apparent bone marrow or splenic involvement on routine light microscopic assessment. Remission was = achieved with single agent rituximab chemotherapy and the patient remained symptom free. The neoplastic CD20 positive epidermotropic B lymphocytes expressed CXCR3. Similar to the prior reported cases by the authors, the neoplastic cells expressed CXCR3, a chemokine whose organ and tissue specific ligands could contribute to its relatively indolent clinicalcourse.

Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma.

BACKGROUND: Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy. METHODS: We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life. RESULTS: A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome ("tumor flare") (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be 85% (95% CI, 67 to 94), and the 2-year overall survival 97% (95% CI, 79 to 99). A response to treatment was associated with improvement in quality of life. CONCLUSIONS: Combination biologic therapy consisting of lenalidomide plus rituximab was active as initial therapy for mantle-cell lymphoma. (Funded by Celgene and Weill Cornell Medical College; ClinicalTrials.gov number, NCT01472562.).

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma.

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m(2) [cycle 1, days 1-2]; 27 mg/m(2) thereafter). This multicenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IV infusion) on days 1, 8, and 15 of 28-day cycles. The phase 1 portion used a 3 + 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at the MTD. Patients received dexamethasone (40 mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 9+. A total of 116 patients were enrolled. The MTD was 70 mg/m(2), and 104 patients (phase 1/2) received carfilzomib 70 mg/m(2) At 70 mg/m(2), the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m(2), the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m(2) was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials.gov as #NCT01677858.

Pediatric oral Epstein-Barr virus associated self-remitting CD30+ lymphoproliferative disorder: A distinct entity.

Epstein-Barr virus (EBV) has a well-known association with lymphoproliferative disorders of B and T cell origin. EBV-related B cell lymphoproliferative disorders include Hodgkin and Burkitt lymphomas, lymphomatoid granulomatosis, EBV positive diffuse large cell B cell lymphoma of the elderly, as well as B cell lymphomas associated with solid organ transplantation and methotrexate use. EBV-related T cell disorders are primarily represented by NK/T- cell lymphoma. In a subset of patients, EBV has been implicated in CD30 positive B cell lymphoproliferative disorders of the oral mucosa falling under the rubric of the mucocutaneous ulcer of the oral cavity. We previously reported on an index series of endogenous CD30 positive T cell lymphoproliferative disorder of the oral cavity resembling borderline type C lymphomatoid papulosis. The clinical manifestation of type C oral lymphomatoid papulosis is that of a recurrent self-remitting ulcer of the oral mucosa, which histologically resembles anaplastic large cell lymphoma. Such cases can be misdiagnosed as aggressive lymphoma leading to unnecessary treatment with aggressive chemotherapeutic regimens. Whereas none of the patients in our index series exhibited EBV positivity, here we discuss a very unique example of a 14-year-old girl diagnosed with EBV positive CD30 positive lymphoproliferative disorder strongly resembling the cases of intra-oral type C lymphomatoid papulosis. The patient was initially diagnosed by a senior hematopathology consultant as having EBV positive aggressive NK/T-cell lymphoma. The significance of raising physician awareness regarding pediatric oral EBV associated CD30 positive lymphoproliferative disease of the oral cavity lies in preventing inadvertent exposure to toxic chemotherapeutic agents intended for treatment of aggressive look-alikes, namely anaplastic large cell lymphoma. Additionally, we include a literature review of similar reports of pediatric intra-oral EBV positive CD30 positive T cell lymphoproliferative disease.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.

Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib.

Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse.

Oral Lymphomatoid papulosis type C: A diagnostic pitfall, often confused with T-cell lymphoma.

Eosinophilic ulcer of the oral mucosa (EUOM) is a rare, benign, self-resolving lymphoproliferative disorder, which typically presents with asymptomatic to mildly tender ulcers. Histological findings of EUOM are characterized by a polymorphic infiltrate with many eosinophils often extending into the underlying muscle. Although this entity is well documented within the dental literature, it is not well known to physicians. The pathogenesis of the condition is unclear, although reports dating back to 1997 suggest that at least a subset of EUOM represents CD30 positive lymphoproliferative disorder (CD30+ LPD). More specifically the original report and subsequent authors suggest that the patients fall on the spectrum of CD30+ LPD most reminiscent of Lymphomatoid papulosis (LyP) seen in the skin. This oral variant of LyP would be expected to have the same diverse morphologic spectrum as that seen in cutaneous LyP. We present five EUOM patients whose biopsies showed an atypical lymphocytic infiltrate most compatible with Type C LyP, a histologically unique subset of LyP, reminiscent of the biopsy findings encountered in the reported case by Ficarra and co-workers. (Ficarra, et al., 1997) In four of the five cases, the biopsies were interpreted by expert hematopathologists as an aggressive form of peripheral T cell lymphoma resulting in recommendations to administer systemic chemotherapy to four of the patients, the scheduling of one patient for induction therapy and transplantation before revision of the diagnosis, and administration of chemotherapy to one of the patients. The natural clinical course of spontaneous regression refuted the original diagnoses as a form of aggressive peripheral T cell lymphoma. Recognition of oral LyP is critical to avoid inadvertent exposure to potentially toxic chemotherapeutic regimens intended for the treatment of high grade lymphoma.

Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.

BACKGROUND: The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. METHODS: We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. RESULTS: Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. CONCLUSIONS: Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).

BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma.

The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.

BACKGROUND: Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. METHODS: In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. FINDINGS: Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22.1 months (IQR 18.4-23.2), 22 (71%) of 31 patients achieved an objective response (95% CI 52.0-85.8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. INTERPRETATION: The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. FUNDING: Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.

Characterization of ibrutinib-sensitive and -resistant mantle lymphoma cells.

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.

The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale.

A retrospective, international, multicenter study was undertaken to assess: (i) the prognostic role of 'interim' positron emission tomography performed during treatment with doxorubicin, bleomycin, vinblastine and dacarbazine in patients with Hodgkin lymphoma; and (ii) the reproducibility of the Deauville five-point scale for the interpretation of interim positron emission tomography scan. Two hundred and sixty patients with newly diagnosed Hodgkin lymphoma were enrolled. Fifty-three patients with early unfavorable and 207 with advanced-stage disease were treated with doxorubicin, bleomycin, vinblastine and dacarbazine ± involved-field or consolidation radiotherapy. Positron emission tomography scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. An international panel of six expert reviewers independently reported the scans using the Deauville five-point scale, blinded to treatment outcome. Forty-five scans were scored as positive (17.3%) and 215 (82.7%) as negative. After a median follow up of 37.0 (2-110) months, 252 patients are alive and eight have died. The 3-year progression-free survival rate was 83% for the whole study population, 28% for patients with interim positive scans and 95% for patients with interim negative scans (P<0.0001). The sensitivity, specificity, and negative and positive predictive values of interim positron emission tomography scans for predicting treatment outcome were 0.73, 0.94, 0.94 and 0.73, respectively. Binary concordance amongst reviewers was good (Cohen's kappa 0.69-0.84). In conclusion, the prognostic role and validity of the Deauville five-point scale for interpretation of interim positron emission tomography scans have been confirmed by the present study.

A phase 1 study of bendamustine and melphalan conditioning for autologous stem cell transplantation in multiple myeloma.

Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200 mg/m(2). Twenty-five subjects were enrolled into 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225 mg/m(2) + melphalan 200 mg/m(2) was expanded to further evaluate safety. Overall, there was no transplant related mortality and only one grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment were 11 (range, 9 to 14) and 13 (range, 10 to 21), respectively. Disease responses at day +100 posttransplantation were progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with pre-existing high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after autologous stem cell transplant. Bendamustine up to a dose of 225 mg/m(2) added to autologous stem cell transplantation conditioning with high-dose melphalan in patients with multiple myeloma did not exacerbate expected toxicities.