Malte Leithäuser

High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial

BACKGROUND High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. METHODS Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m(2)) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m(2)) on days 3-5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. FINDINGS 551 patients (median age 63 years, IQR 55-69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8-39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5-46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80-1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6-25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3-16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). INTERPRETATION No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors.

Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.

BACKGROUND Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD. METHODS In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548. FINDINGS 74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79·1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6·6 years (95% CI 2·8-10·4; n=70). INTERPRETATION Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD. FUNDING F Hoffmann-La Roche, Amgen Germany, Chugaï France.

Rapid and sustained clearance of circulating lymphoma cells after chemotherapy plus rituximab: clinical significance of quantitative t(14;18) PCR monitoring in advanced stage follicular lymphoma patients†

This study of first‐line treatment in advanced‐stage follicular lymphoma patients analysed the effects of MCP (mitoxantrone, chlorambucil and prednisolone) chemotherapy alone or in combination with rituximab (R‐MCP) on circulating lymphoma cells (CLC) and assessed the prognostic value of a quantitative monitoring of CLC. CLC numbers were determined by quantitative polymerase chain reaction (PCR) for the t(14;18)‐translocation or by allele‐specific PCR for rearranged immunoglobulin heavy chain genes. We analysed blood samples from 43 patients treated in a randomized trial comparing eight cycles of MCP versus R‐MCP. Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R‐MCP compared with 0/18 after MCP alone (P < 0·0001). A ≥2 log CLC reduction was associated with a favourable clinical response (P = 0·0004) and prolonged event‐free survival (P = 0·02). In R‐MCP patients, stable CLC numbers or consistently PCR‐negative blood samples were associated with a continuing clinical remission whereas in two patients a relapse was preceded by a ≥2 log CLC increase. This study demonstrated that R‐MCP led to a rapid and sustained eradication of CLC and a ≥2 log CLC reduction was associated with a superior quality and duration of the clinical response.

International Prognostic Index, Type of Transplant and Response to Rituximab Are Key Parameters to Tailor Treatment in Adults With CD20‐Positive B Cell PTLD: Clues From the PTLD‐1 Trial

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD‐1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP‐based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low‐risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

Invasive zygomycosis in patients with graft-versus-host disease after allogeneic stem cell transplantation.

M. Leithauser, C. Kahl, C. Aepinus, F. Prall, M. Maruschke, H. Riemer, D. Wolff, K. Jost, I. Hilgendorf, M. Freund, C. Junghanss. Invasive zygomycosis in patients with graft‐versus‐host disease after allogeneic stem cell transplantation
Transpl Infect Dis 2010: 12: 251–257. All rights reserved

Perforation of the Superior Vena Cava – a Rare Complication of Central Venous Catheters

Background: Central venous catheters (CVC) guarantee a reliable venous access and are an indispensable part of the therapy in patients with hematologic malignancies. On the other hand, they contribute significantly to the therapy-related morbidity in this group of patients. The most common complications are catheter-associated infections or thromboses. Here we report on the rare, but potentially life-threatening case of a vessel wall perforation by a CVC. Case Report: A 29-year-old female with newly diagnosed acute lymphoblastic leukemia had a CVC inserted via the left subclavian vein. After two weeks she complained about acute chest pain. Radiology revealed right-sided pleural effusion which was due to a vena cava superior vessel wall perforation by the CVC. Chemotherapy extravasation was excluded by pleural fluid analyses. Conclusion: A vessel wall perforation by a CVC is a rare and often late CVC complication with usually unspecific symptoms. Especially patients with leftsided, large-bore catheters are at risk. Awareness of this complication and immediate therapy are essential. We discuss the possible mechanisms and treatment options of this rare CVC complication.

Multimodal Therapy for Localized Spinal Epidural Follicular Lymphoma

Background: Myelopathy due to epidural spinal cord compression is rare in patients with malignant lymphoma and most of these patients are diagnosed with high-grade lymphoma. An epidural growth of low-grade lymphoma is even more unusual. Due to this low incidence, therapeutic experience for this entity is limited. Patients and Methods: We report the outcome of 3 consecutive patients with primary spinal epidural follicular lymphoma (FL). Due to the clinical disorders of the patients and despite the localized disease, we used an intensive multimodal therapy concept consisting of spinal decompression, systemic (immuno)chemotherapy and local irradiation. All patients improved in their medical condition; 2 achieved a complete remission, 1 of these with long-term remission. Conclusions: In contrast to the established irradiation therapy for early-stage FL, an intensive multimodal therapy concept should be initiated in patients with primary spinal epidural FL. With this approach, a fast improvement of the symptoms and long-term disease-free survival is possible.

Baseline differential blood count and prognosis in CD20-positive post-transplant lymphoproliferative disorder in the prospective PTLD-1 trial.

Baseline differential blood count and prognosis in CD20-positive post-transplant lymphoproliferative disorder in the prospective PTLD-1 trial

Chronic Graft versus Host Disease but not the Intensity of Conditioning has Impact on Survival after Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Hematological Diseases

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is often performed in cases of advanced hematological diseases, but because of the associated mortality and a high risk of relapse it is life prolonging only in some patients. Patients and Methods: A retrospective multi-center analysis of 401 patients was conducted to analyze the variables associated with outcome after alloHSCT in advanced hematological diseases. The Cox proportional hazards model was used to assess the independence of overall survival (OS) and disease-free survival (DFS) from prognostic factors in a multivariate model. Results: The 5-year OS and DFS were 27.3 and 21.1% respectively. Multivariate analysis showed that the underlying malignancy had a significant influence on OS and DFS (p < 0.001 and p < 0.011, respectively), whereas development of severe acute graft versus host disease (GvHD) had a negative impact on OS (p < 0.001). Development of chronic GvHD showed a trend to a better OS (p = 0.085) and DFS (p = 0.199). No impact was seen for the intensity of conditioning. Conclusion: Development of chronic GvHD but not the conditioning regimen improved the outcome after alloHSCT for advanced malignancies, underlining the importance of immunological rather than cytotoxic effects.

Treatment with campath-1H for relapsed chronic lymphocytic leukemia after allogeneic peripheral blood stem cell transplantation does not abrogate the development of chronic GVHD.

The graft vs. leukemia (GVL) effect is one of the most important factors of anti‐tumor activity after allogeneic hematopoetic stem cell transplants (alloSCT). Its effectiveness depends mainly on the tumor biology as well as the tumor burden. Patients with a high tumor burden may not respond to GVL‐effect despite otherwise sensitive biology. Campath‐1H is known as an effective treatment of chronic lymphocytic leukemia (CLL). Due to its ability to induce profound immunosuppression, it has also been used as part of conditioning regimens before alloSCT. We report a patient, who received campath‐1H in combination with docetaxel for treatment of chemotherapy and donor lymphocyte infusion resistant CLL after alloSCT, who developed shortly after discontinuation of treatment with campath‐1H severe eosinophilia of the peripheral blood and typical clinical as well as histological signs of cutaneous chronic graft vs. host disease followed by complete clearance of CLL. The clinical course demonstrates the impact of the tumor burden on the GVL‐effect, as well as the effectiveness of campath‐1H in the presence chemo‐resistance in a patient with CLL. Furthermore, the GVL effect was not abrogated by the use of campath‐1H.