A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL

The purpose of this study is to assess the safety and efficacy of the combination of ofatumumab and bendamustine in patients with previously untreated or relapsed chronic lymphocytic leukemia. Patients received IV ofatumumab (cycle 1: 300 mg day 1 and 1,000 mg day 8; cycles 2–6: 1,000 mg on day 1 every 28 days) and IV bendamustine 90 mg m^?2 (previously untreated) or 70 mg m^?2 (relapsed) on days 1 and 2 of each 28‐day cycle, for up to 6 cycles. Forty‐four previously untreated and 53 relapsed patients were enrolled. Median age was 62.5 years (previously untreated) and 68 years (relapsed); relapsed patients had received a median of 1 (range 1–11) prior therapy. The investigator‐assessed overall response rate was 95% (43% complete response [CR]) for the previously untreated, and 74% (11% CR) for the relapsed patients. The regimen was well tolerated with 89% (previously untreated) and 85% (relapsed patients) receiving all 6 cycles. No unexpected toxicities were reported. Grade 3/4 events occurred in 57% of previously untreated, and 72% of relapsed patients. At ～29 months’ follow‐up, the median progression‐free survival (PFS) was not reached for the previously untreated population, and the 28‐month PFS estimate was 72.3%. The median PFS for the relapsed population was 22.5 months (95% CI: 14.0–27.3 months). The combination of ofatumumab and bendamustine was well tolerated and effective in these previously untreated or relapsed populations. Am. J. Hematol. 91:900–906, 2016. © 2016 Wiley Periodicals, Inc.     

Guidelines for the management of diffuse large B‐cell lymphoma

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.     

Low‐dose alemtuzumab in refractory/relapsed chronic lymphocytic leukemia: Genetic profile and long‐term outcome from a single center experience

Relapsed/refractory chronic lymphocytic leukemia (CLL) represents a clinical challenge, in particular when high risk gene mutations occur. In this setting, alemtuzumab was recognized to be effective. This retrospective study evaluates long‐term efficacy and tolerability of low‐dose alemtuzumab in relapsed/refractory CLL and correlates clinical outcome with biological feature. Sixty‐two consecutive patients (median age 68 years) were evaluated; alemtuzumab was administered 30 mg weekly for up to 18 weeks. Among the patients included in the analysis, 37% were fludarabine‐refractory, 33.3% carried a TP53 disruption, 14.8% a NOTCH1 mutation and 9% a SF3B1 mutation. Overall response rate (ORR) was 61.3% (complete remission 25.8%). After a median follow‐up of 43 months, overall survival (OS) and progression free survival (PFS) were 43.1 and 15 months, respectively; while ORR was 77.8% for patients carrying TP53 disruptions (OS 33.8 months) and 43.5% for fludarabine‐refractory patients (OS 30 months). Noteworthy, long‐term survivors (OS ≥ 36 months) were 54.8%. None of the biological poor risk factors negatively impacted on ORR, PFS and OS. Grade ≥3 cytopenia occurred in 24.2% patients, 6.5% experienced a grade ≥3 non‐CMV infection and no grade ≥3 CMV‐event occurred. In conclusion, low dose‐alemtuzumab is safe and effective in relapsed/refractory CLL, also in a long‐term follow‐up and high‐risk genetic subgroups. Am. J. Hematol. 90:970–974, 2015. © 2015 Wiley Periodicals, Inc.     

Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory,indolent non‐Hodgkin lymphoma

This phase II study evaluated the safety and efficacy of lenalidomide in combination with rituximab in patients with relapsed/refractory, indolent non‐Hodgkin lymphoma (NHL). Patients were treated with daily lenalidomide in 28‐d cycles and weekly rituximab for 4 weeks. Lenalidomide was continued until progression or unacceptable toxicity. Twenty‐two patients were assessed for FCGR3A polymorphisms. Thirty patients were enrolled; 27 were evaluable for response. The overall response rate (ORR) was 74% including 44% complete responses (CR); median progression‐free survival (PFS) was 12·4 months. The 13 rituximab refractory patients had an ORR of 61·5% (four CR/unconfirmed CR). The ORR was 77% in the 22 follicular lymphoma patients (nine CR/unconfirmed CR). At a median follow‐up time of 43 months, the median duration of response and time to next therapy were 15·4 and 37·4 months, respectively. Most common grade 3/4 adverse events were lymphopenia (45%), neutropenia (55%), fatigue (23%) and hyponatraemia (9%). The ORR and PFS in patients with low‐affinity FCGR3A polymorphisms (F/F and F/V) suggest that lenalidomide may improve the activity of rituximab in these patients. These data suggest that combining lenalidomide with rituximab can produce durable responses with acceptable toxicity in patients with indolent NHL.     

A phase 2 study of modified lenalidomide,bortezomib and dexamethasone in transplant‐ineligible multiple myeloma

We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m² weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population.     

Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia

We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had β2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, β2-microglobulin and the number of O-FC courses were significantly correlated (P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at www.clinicaltrials.gov as NCT00410163.     

A phase II study of two dose levels of ofatumumab induction followed by maintenance therapy in symptomatic,previously untreated chronic lymphocytic leukemia

Despite the recent advances in treatment of CLL with targeted agents such as ibrutinib, availability of nonchemotherapy based therapies is desired. Given the 58% response rate (1996 NCI‐WG criteria) of single agent ofatumumab in CLL refractory to fludarabine and alemtuzumab, we initiated a phase II trial examining response, safety, and progression‐free survival (PFS) of ofatumumab as front‐line monotherapy. Patients enrolled included untreated, symptomatic CLL patients over the age of 65 or those who were inappropriate/did not desire chemotherapy. Two cohorts were enrolled sequentially examining either 1 g (33 patients) or 2 g (44 patients) weekly for 8 weeks followed by maintenance dosing every 2 months for a total of 24 months. Patients receiving 1 g were older than those receiving 2 g, but there were no significant differences in other clinical characteristics. The best overall response rates in the 1 and 2 g patient cohorts were 72 and 89% (1996 NCI‐WG criteria), respectively (54 and 68%, respectively, using 2008 IWCLL criteria). All but two responses were partial. The 24‐month estimated PFS rates were 46 and 78%, respectively. Response and PFS was lower in del(17p) and del(11q) CLL patients. Differences in PFS between dose cohorts were statistically significant and remained so when adjusting for age or high‐risk cytogenetics. Toxicity of this treatment was mild with only six patients not completing therapy due to toxicity. Ofatumumab induction followed by maintenance therapy in untreated CLL represents a well‐tolerated and active regimen, particularly with the 2 g of ofatumumab. Am. J. Hematol. 91:1020–1025, 2016. © 2016 Wiley Periodicals, Inc.     

Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).     

The addition of dexamethasone to bortezomib for patients with relapsed multiple myeloma improves outcome but ongoing maintenance therapy has minimal benefit

Despite the common practice of combining dexamethasone (Dex) with bortezomib (Bz) in patients with multiple myeloma (MM), until now there has been few prospective trials undertaken. We undertook a trial that recapitulated the original APEX study except that dexamethasone was incorporated from cycle 1. We also incorporated an exploratory maintenance component to the study. Twenty sites enrolled 100 relapsed/or refractory MM patients utilizing eight 21 day cycles of IV Bz [1.3 mg/m²; Day (D) 1, 4, 8, 11] and three 35 day cycles; Bz (1.3 mg/m²; Day (D) 1, 8, 15, 22). Our study was registered at www.clinicaltrials.gov (NCT00335348). Patients with stable disease or better received maintenance Bz (1.3 mg/m²) every 14 days until progression. Dexamethasone (20 mg) was given for 2 days with each Bz dose. A prospectively defined matched‐analysis of primary (overall response rate; ORR) and secondary endpoints [Complete Response (CR) and time to progression (TTP)] compared our cohort to those on the Bz arm of the APEX trial. The addition of Dex improved ORR by 20% (56% vs. 36%) [odds ratio 0.44 (0.24–0.80)]. The median TTP was also significantly longer (10.1 vs. 5.1 months) (hazard ratio 0.50, 95% CI: 0.35‐0.72, P = 0.0002) and our landmark analysis demonstrated that this was largely due to the early use of dexamethasone, as we were unable to demonstrate any benefit of bortezomib/dexamethasone maintenance therapy. Am. J. Hematol. 90:E86–E91, 2015. © 2015 Wiley Periodicals, Inc.     

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed,refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study

Bendamustine + rituximab (BR) has demonstrated high response rates in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). However, progression‐free survival (PFS) after BR is <18 months. This study was designed to determine if maintenance lenalidomide after BR induction could improve PFS in R/R CLL/SLL. Thirty‐four patients with R/R CLL/SLL who had received 1–5 prior chemotherapy regimens were treated with 6 cycles of BR induction. Patients achieving at least a minor response received twelve 28‐d cycles of lenalidomide 5–10 mg/d. The primary endpoint was PFS. The median age was 67 years, with a median of 2 prior therapies. Eleven patients had confirmed presence of 17p and/or 11q deletions. Twenty‐five (74%) completed 6 cycles of induction BR (response rate 56%). Nineteen (56%) patients received maintenance lenalidomide; only 6 patients completed the intended 12 cycles, highlighting the limited feasibility of lenalidomide in this setting, primarily due to haematological and infectious toxicities. The observed median PFS of 18·3 months is not significantly different from that of BR induction in R/R CLL/SLL without maintenance therapy (15·2 months). It is possible that lenalidomide maintenance may be more feasible and effective in the front‐line setting, which is being tested in an ongoing trial (NCT01754857).     

Effectiveness of gemcitabine,pegaspargase, cisplatin,and dexamethasone (DDGP) combination chemotherapy in the treatment of relapsed/refractory extranodal NK/T cell lymphoma: a retrospective study of 17 patients

The prognosis of extranodal nature killer (NK)/T cell lymphoma (ENKL) is dismal because of its aggressive course and multidrug resistance. Currently, for patients with relapsed/refractory ENKL, l-asparaginase-based regimens such as l-asparaginase, ifosfamide, methotrexate, etoposide, and dexamethasone (SMILE) or l-asparaginase, methotrexate, and dexamethasone (AspaMetDex) are recommended. We retrospectively investigated the efficacy and safety of gemcitabine, pegaspargase, cisplatin, and dexamethasone (DDGP) combination chemotherapy in the treatment of 17 relapsed/refractory ENKL patients. Clinical data from these patients were collected and analyzed. The primary end point was overall response rate (ORR). All patients were subjected to 2 to 6 cycles of DDGP chemotherapy, and the median number of cycles of DDGP regimen administrated was four. The ORR was 88.2 % (15/17), with nine patients (52.9 %) achieved complete response (CR) and six patients (35.3 %) achieved partial response (PR). The median follow-up time was 17 months (range 2–28 months). The 1-year overall survival (OS) rate and 1-year progression-free survival (PFS) were 82.4 and 64.7 %, respectively. For those CR responders, the median PFS was 17 months. Grade 3/4 neutropenia occurred in nine patients (52.9 %) and grade 3/4 thrombocytopenia occurred in six patients (35.3 %). DDGP combination chemotherapy produces favorable outcomes in relapsed/refractory ENKL, and more attention should be paid to treatment-related myelosuppression. Further prospective trials are expected to define the efficacy.     

Salvage treatment with upfront melphalan 100 mg/m2 and consolidation with novel drugs for fulminant progression of multiple myeloma

Patients (pts) with fulminant progression (FPG) of multiple myeloma (MM) after autologous stem cell transplantation (ASCT) have poor prognosis. Pancytopenia, extramedullary disease, and/or renal impairment are often present, and treatment options are limited. We have retrospectively evaluated 31 pts with FPG of MM after ASCT who were treated upfront salvage therapy with melphalan 100 mg/m² (MEL 100) followed by PBSC support and consolidation therapy using regimens containing thalidomide (n?=?16) or bortezomib (n?=?15). The overall response rate (ORR) was 58% (18/31). After MEL 100, one patient achieved complete remission (3%), 26% of pts very good partial remission, 29% of pts partial remission, and 42% of pts stable disease. Progression within 3 months after MEL 100 occurred in 35% of pts. The median follow-up from MEL 100 was 8 months. The median TTP was 5 months (range, 2–15 months), and the median OS was 8 months (range, 3–23 months). There were no treatment-related deaths. In fulminant progression of MM, upfront MEL 100 is a safe salvage regimen with good response rate (ORR, 58%). Treatment with upfront MEL 100 followed by a thalidomide- or bortezomib-based regimen can prolong overall survival to more than 12 months in 33% of pts with fulminant progression of MM.     

Good clinical activity and favorable toxicity profile of once weekly bortezomib,fotemustine, and dexamethasone (B‐MuD) for the treatment of relapsed multiple myeloma

Since multiple myeloma (MM) is still not‐curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B‐MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80–100 mg/m² i.v.) on day 1. The original 21‐day schedule was early amended for extra‐hematological toxicity and a 35‐day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty‐four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression‐free survival (PFS) was 19.1 months. B‐MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib‐naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B‐MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase. © Am. J. Hematol., 88:102–106, 2013. © 2012 Wiley Periodicals, Inc.     

Salvage therapy for acute myeloid leukemia with fludarabine,cytarabine, and idarubicin with or without gemtuzumab ozogamicin and with concurrent or sequential G‐CSF

The current salvage therapies for relapsed/refractory acute myeloid leukemia (AML) are unsatisfactory. Over the past 7 years, we have used two salvage regimens: fludarabine, cytarabine, and idarubicin with (FLAG‐IM) or without gemtuzumab ozogamicin (GO) (9 mg/m² on Day 8) (FLAG‐I) in relapsed/refractory AML. Three‐quarters of patients also received concurrent G‐CSF. Seventy‐one patients were treated, 23 with FLAG‐I and 48 with FLAG‐IM. The median duration of follow‐up was 30.6 months. The treatment groups were well balanced with median ages of 48 years (range 18–70) and 47 years (range 20–68), unfavorable cytogenetics in 57% and 35%, prior allogeneic stem cell transplant in 43% and 42%, and CR1 duration <1 year in 60% and 67%, respectively, for FLAG‐I and FLAG‐IM. The complete remission (CR) rate in the FLAG‐I group was 39% with an additional 13% achieving a CRp [overall response rate (ORR) 52%]; the CR rate in the FLAG‐IM group was 29% with an additional 27% achieving a CRp (ORR 56%). The median duration of response (DOR; 16.8 vs. 8.3 months), event‐free survival (EFS; 7.4 vs. 4.1 months), and overall survival (OS; 8.8 vs. 5.0 months) trended to favor FLAG‐I over FLAG‐IM. The patients who received G‐CSF concurrent with chemotherapy had superior overall response rate (ORR; 62% vs. 29%, P = 0.026), median EFS (6.2 vs. 3.4 months, P = 0.010), and OS (8.8 vs. 3.9 months, P = 0.004) when compared with those who sequentially received G‐CSF and chemotherapy, regardless of chemotherapy regimen. The addition of GO, at this dose and schedule, to FLAG‐I failed to improve the outcomes in patients with relapsed/refractory AML. The patients who received G‐CSF concurrently with chemotherapy had improved outcomes. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

Clinical activity of a new regimen combining gemcitabine and alemtuzumab in high‐risk relapsed/refractory chronic lymphocytic leukemia patients

Optimal treatment strategies are lacking in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Gemcitabine has shown activity and acceptable safety profile in B‐cell lymphomas. We present a retrospective case review of gemcitabine and alemtuzumab, every 21 d (for up to six courses) in 27 community‐based patients with high‐risk R/R CLL. Median age was 70 yr (44–83 yr), 55% patients had Binet stage C, deletion 17p (del(17p)) and/or deletion 11q (del(11q)) were found in 65% and 27%, bulky disease in 55.5%, and fludarabine‐refractoriness in 48% of cases, respectively. Overall response rate was 63% (29.6% clinical CR and 33.4% PR). At a median follow‐up of 31 months, median PFS and OS were 15.4 and 24 months. In multivariate analysis, median OS is influenced by prior lines of treatment = 3 and bulky disease. Combination of alemtuzumab and gemcitabine appears to be an active, easy to administrate treatment in routine practice, high‐risk R/R CLL patients.     

Phase II study of ifosfamide, etoposide, and oxaliplatin (IFETOx) chemotherapy for relapsed or refractory non-Hodgkin’s lymphoma

As part of an effort to develop a more effective and safe treatment for relapsed or refractory non-Hodgkin’s lymphoma (NHL), we conducted a phase II study of the oxaliplatin, etoposide, and ifosfamide (IFETOx) regimen. Patients with relapsed or refractory NHL and a performance status of 0–2 were eligible. The IFETOx consisted of etoposide at 100 mg/m² on days 1–3, oxaliplatin at 130 mg/m² on day 2, and ifosfamide 5,000 mg/m² on day 2, every 21 days. The primary endpoint was the overall response rate (ORR) for IFETOx regimen. A total of 23 eligible patients were enrolled. The median age was 58 years (range 19–76 years), and the male-to-female ratio was 15:8. The disease status was as follows: 15 patients had relapsed and 8 patients were refractory to treatment. The ORR for IFETOx chemotherapy was 65.2 %. In the 15 patients who responded to the protocol treatment, five underwent hematopoietic stem cell transplantation. The 2-year probability of progression-free survival and overall survival rates were 51.4 and 56.1 %, respectively. Grade 3/4 neutropenia was observed in 73.9 % of the patients. No significant renal impairment was observed. In conclusion, IFETOx chemotherapy shows a tolerable toxicity profile and efficacy as a salvage treatment regimen for relapsed or refractory NHL.     

A phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and 90yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B‐cell non‐Hodgkin lymphoma

Radioimmunotherapy (RIT) for relapsed indolent non‐Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B‐cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial, we tested systemic administration of both CpG and RIT. Eligible patients had biopsy‐proven previously treated CD20+ B‐cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m² days 1,8, and 15; ¹¹¹In‐ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of ⁹⁰Y‐ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hr without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18‐NR); and median duration of response (DR) of 35 months (4.6–76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation. Am. J. Hematol. 88:589–593, 2013. © 2013 Wiley Periodicals, Inc.     

Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma

An international, Phase II trial was conducted to assess two doses of ofatumumab, a human CD20 monoclonal antibody, combined with cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), prednisone (100 mg days 3–7) and vincristine (1·4 mg/m²) (O‐CHOP), as frontline treatment for follicular lymphoma (FL). 59 patients with previously untreated FL were randomized to ofatumumab 500 mg (n = 29) or 1000 mg (n = 30) day 1, with CHOP on day 3 every 3 weeks for six cycles. Median duration of FL was 0·1 years for both dose groups; 34% and 38% of patients had high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) scores in the 500‐ and 1000‐mg dose groups, respectively. Overall response rate was 90% for the 500‐mg group and 100% for the 1000‐mg group. 62% of patients achieved complete response (CR)/unconfirmed CR (CRu). 76% of patients with FLIPI score 3–5 attained CR/CRu. Longer follow‐up time is needed for analysis of survival end points. The most common Common Terminology Criteria grade 3–4 investigator‐reported adverse events were leucopenia (29%) and neutropenia (22%). No deaths have been reported. O‐CHOP was safe and efficacious in patients with previously untreated FL, including high‐risk FLIPI groups. This trial was registered at www.clinicaltrials.gov (NCT00494780).     

Phase II study of methotrexate,vincristine, pegylated‐asparaginase,and dexamethasone (MOpAD) in patients with relapsed/refractory acute lymphoblastic leukemia

Newer approaches are needed for the treatment of relapsed and refractory acute lymphoblastic leukemia (ALL). Asparaginase‐based regimens are active in the treatment of pediatric ALL and may be important in salvage therapy for adult patients. We conducted a pilot trial combining methotrexate, vincristine, PEGylated‐asparaginase, and dexamethasone (MOpAD) in adults with relapsed or refractory ALL. We added tyrosine kinase inhibitors in patients with Philadelphia chromosome positive (Ph+) ALL and rituximab in patients with CD20 positive B‐cell ALL. Among 37 patients treated (median age 42 years; median 2 prior therapies), the complete remission (CR) rate was 28% and an overall response rate (ORR) was 39%. The median CR duration was 4.3 months. Patients with Ph+ ALL had CR and ORR of 50% and 67%, respectively and the CR and ORR in patients with T‐cell leukemia were 45% and 56%, respectively. The median survival in patients with CR/CRp was 10.4 versus 3.4 months in nonresponders (P = 0.02). The most common grade 3 or 4 nonhematologic toxicities were elevations in bilirubin and transaminases, nausea, peripheral neuropathy, and hyperglycemia, which were managed with supportive care, dose adjustments, and interruptions. Am. J. Hematol. 90:120–124, 2015. © 2014 Wiley Periodicals, Inc.     

Autologous stem cell transplantation in advanced follicular lymphoma. A single center experience

BACKGROUND AND OBJECTIVE: The use of intensive therapy supported by autologous stem cell transplantation (ASCT) is being investigated as treatment for poor-prognosis follicular lymphomas (FL). A single-center experience is herein reported. DESIGN AND METHODS: From September 1990 to October 1997, 30 consecutive patients (pts) with advanced FL received transplants, 8 of bone marrow and 22 of peripheral blood. Thirteen harvests were purged by an immunomagnetic method using anti-B antibodies. Twenty-seven patients received salvage chemotherapy (CT) before ASCT with the objective of reaching this procedure in the best possible response. The disease status at ASCT was: 1(st) CR in 7 pts, > or =2(nd) CR in 6 pts, PR in 10 pts, untreated relapse in 2 pts and chemoresistant disease in 5 pts. RESULTS: There was only one transplant-related death (one month after ASTC). With a median follow-up of 19 (1-89) months, 27 pts are alive, 8 pts have relapsed/progressed at a median time of 11 (6-22) months after ASCT. The estimated 2-year PFS and OS are 57% (95% CI, 34-81%) and 83% (95% CI, 64-100%). When comparing the progression-free interval (PFI) before salvage CT and ASCT and the PFI after ASCT, of 17 evaluable pts, 10 had a PFI after ASCT longer than the previous interval, and 5 additional pts remain in CR/PR with a follow-up that has not yet reached the duration of pre-transplant response. By contrast, 2 pts had a short post-transplant response. INTERPRETATION AND CONCLUSIONS: High-dose therapy followed by ASCT obtains a high rate of responses, frequently longer than any previous PFI. Additional follow-up is necessary to determine whether there is any "plateau" in response duration and to define what proportion of pts may be cured with ASCT in this setting.