Timing and complications of allogeneic stem cell transplant in Ph + ALL

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1 Timing and complications of allogeneic stem cell transplant in Ph + ALL Dr Ashlea Campbell Haematology Advanced Trainee Concord Repatriation and General Hospital Royal Prince Alfred Hospital 24 th Feb 2017

2 Disclosures No affiliations to disclose

3 Introduction Philadelphia positive ALL (Ph+ALL) has traditionally been thought to have a poor prognosis. Tyrosine kinase inhibitors (TKIs) have improved initial CR rates and possibly long term outcomes however allogeneic stem cell transplant remains standard of care in aiming for long term remission. The survival rate following transplant in first CR is higher than in subsequent CRs (1) and this remains the goal of treatment however is not always achievable. Presenting the case of Mr MK

4 Initial presentation Mr MK, 33 yr old, who works in IT, originally from Korea. Has one brother and supportive parents. Diagnosed with Ph+ ALL in May 2014

5 Initial treatment HyperCVAD (+ Rituximab) and Imatinib commenced June 2014 Achieved molecular remission after cycle 1 Brother tissue typed Referred to transplant haematologist

6 Transplant options Brother not a match MUD search commenced MUD donor found but unfortunately declined Double cord transplant considered at this time but cell numbers were borderline ~ 1.5x10 7 and thought to increase risk of morbidity and mortality

7 Progress Completed 8 cycles of HyperCVAD and continued Imatinib 600mg daily Finished December 2014 Remained in morphological and molecular CR

8 Relapse on maintenance During monitoring while on maintenance Imatinib PB BCR-ABL in March 2015: 0.001% (previously undetectable) At same time presented to clinic with headaches and meningism

9 Systemic and CNS Relapse MRI Brain: leptomeningeal enhancement consistent with leukaemic infiltration CSF flow: 88% lymphoblasts consistent with CNS B- ALL Circulating blasts in peripheral blood

10 Reinduction Imatanib changed to Dasatinib High dose methotrexate (3.5g/m 2 ) commenced with cytarabine (2g/m) and Vincristine Weekly IT therapy

11 Reinduction BM May 2016: Morphological remission but CSF remained positive on flow cytometry PB BCR-ABL also now undetectable CSF cleared by June with ongoing IT, dexamethasone & dasatinib

12 Transplant Double cord transplant July 2015 Stem cell dose 1.8 x 10 7 /kg Cyclophosphamide and total body irradiation (TBI 1200 Gy over 6#) myeloablative conditioning Immunosuppression consisted of Cyclosporin Mycophenolate

13 Complications during transplant period Neutropenic sepsis, right eye pain & swelling Imaging showed extensive sinus disease with a breach of medial wall of orbit (Day + 8) Progressive visual loss, ophthalmoplegia (Day + 14) Persistent fevers despite multiple antimicrobials (Tazocin, Amikacin, Daptomycin, Meropenum Amphotericin)

14 Orbital and sinus invasive fungal infection T1 Image with high signal material in the sinuses

15 Orbital and sinus invasive fungal infection Diagnosis: invasive aspergillus infection affecting the sinuses and right orbit with extension into the anterior cranial fossa with secondary encephalitis Multiple ophthalmalogical surgeries required R orbital decompression; no return in vision, persistent fevers and aspergillus on tissue specimen (Day +15) Required R orbital exenteration and debulking surgery Surgery complicated by CSF leak

16 Orbital fungal infection Amphotericin changed to voriconazole Orbital & sinus infection complicated by a cerebral abscess in the inferior right frontal lobe Resulted in two R frontal craniotomies to remove the skull base abscess

17 Post operative MRI T2 Image showing inflammatory change post operatively

18 Post operative MRI T2 Image showing residual cerebral abscess (fungal infection)

19 Other complications Depression Significant deconditioning Neutropenic colitis (no evidence of GVHD or CMV infection on biopsy) Delayed engraftment (Day +25) Prolonged thrombocytopenia Appendicectomy (Day +45) for ongoing abdominal pain, diarrhea and suggestion of appendicitis on CT scan. This diagnosis was not confirmed on histology. Prolonged nausea, vomiting and malnutrition (gastric biopsy showed chronic gastritis, no evidence of GVHD). Albumin nadir < 20g/L Total admission time 126 days

20 Progress post transplant Oral voriconazole for 1 year Immunosuppression weaned Bone marrow biopsy Day showed morphological and cytogenetic remission PB BCR-ABL transcripts undetectable Participated in post-transplant rehabilitation program

21 Post transplant TKI Re-commenced Dasatinib approximately 18 months post transplant Cytopenias and multiple comorbidities prevented restarting a TKI earlier PB BCR-ABL has remained undetectable and he is now 18 months post transplant Mr MK s mood, functional status and quality of life have all significantly recovered post transplant. He is working full time and living independently

22 Questions raised by this case The significant complications and subsequent morbidity that occurred in this case, in the context of prolonged neutropenia and corticosteroid exposure prior to transplant as well as significant comorbidities secondary to prior treatment raise multiple questions

23 1st question When making decisions regarding transplant which factor is the most important? Graft source Timing, aiming for first CR MRD status

24 2nd question Is Philadelphia chromosome positivity still a poor prognostic factor in ALL in the era of TKIs and how does this affect the decision to proceed to allogeneic transplant? There is no robust data to date to suggest that allogeneic transplant no longer has a role however there are studies that have demonstrated long term survival without a transplant. (4,5) Our case would certainly suggest that allogeneic transplant is the optimal treatment given the fulminant relapse following chemotherapy and TKI maintenance

25 3 rd question Given the high rate of CNS relapse in high risk ALL, should we be using a TKI with better CNS penetration upfront? Note that Dasatinib is not available as upfront treatment of Ph + ALL in Australia A Canadian consensus paper in 2014 suggested theoretical advantages of using second generation TKI upfront due to their broader spectrum of activity, higher potency and greater CNS penetration however there is insufficient evidence to date to confirm a benefit. (7) Similarly in 2015 Blood article How I treat acute lympoblastic leukaemia in older adolescents and young adults, they also recommend upfront Dasatinib. (8)

26 Summary The optimal treatment for Ph + ALL in the era of TKIs is controversial and will continue to unfold with further studies and long term data relating to TKI use.

27 Thanks Dr Emma Verner Dr Alessandra Bianchi Associate Professor Stephen Larsen

28 References 1. Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukaemia in adults Up-to-date. R Larsen Porkka K, Koskenvesa P, Lundán T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 2008;112(4): Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375(10): Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med 2014;371: Ravandi F, O Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper- CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood2010;116(12): Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children s oncology group study. J Clin Oncol 2009;27(31): Couban S, Savoie L, Mourad YA, et al. Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome positive or BCR-ABL positive acute lymphoblastic leukemia: a Canadian consensus. Current Oncology. 2014;21(2):e265-e309. doi: /co Curran, E., & Stock, W. (2015). How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood, 125(24),

29 Graft source The majority of patients needing an allogeneic transplant do not have a matched related donor (3). The second choice of stem cell source is generally a 10/10 HLA matched unrelated donor (MUD). However, especially in some ethnic groups, more than 50% of people who do not have a matched sibling donor will also not find a MUD. (4)

30 Graft source

31 Graft source

32 Graft source The survival outcomes in the patients receiving a cord blood transplant were not found to be inferior to those who received a matched MUD transplant.