A 67-year old woman, CML-CP diagnosed September 2017. Presented with blood counts of WCC 300, 3.3% blasts, platelets 1000, baso 6%, big spleen. Marrow blasts <1%. Unsurprisingly was high risk on Sokal. Immediate cytoreduction with HU then imatinib. Her WBC was normal after 3 weeks but she defaulted from follow-up and relapsed having stopped her treatment in mid-2018. After a bit of a pep talk she restarted treatment and regained a haematological response but never any sort of molecular response.

I switched her to dasatinib in November 2018 based on the failure to achieve molecular response. Her mutation screen was negative then.

Her attendance at clinic hasn’t been exemplary and she did stop treatment once but I believe she has been compliant with dasatinib for the last six months based on the pick up of scripts at the right times from her pharmacy.

Another reason for believing she was taking dasatinib was that after several missed blood tests she pitched up in May 2019 with pancytopenia – Hb 63, platelets 36, neutrophils 1.1. Her marrow was virtually aplastic but she still managed to have 23% BCR-ABL on peripheral blood and 100% positive for 9;22 on karyotyping.

I stopped her dasatinib, her blood counts have recovered but her BCR-ABL is back to 43%. Would welcome your advice on where to go next. As well as age not on her side she is a smoker, has had “problematic” drinking in the past, AF and mild heart failure so I don’t think SCT was ever an option.

Andrew Butler
New Zealand

Hi Andrew,

Tough challenge! I asked my colleagues for their opinions:

David Yeung: I think this is one of the most difficult scenarios. TKI on = Aplasia. TKI off = untreated CML. We’ve seen several cases now with patients having transfusion / GCSF dependent cytopenias whilst on TKIs, and persistent / patient transfusion support whilst persisting with TKI had not managed to bring about marrow recovery with Ph negative haematopoiesis. There’s also been a couple of patients in this category at other sites that we know of, through our conduct of TIDEL-II. I guess one can hypothesise about lack of a normal, Ph neg stem cell compartment in these patients. Switching TKIs does not seem to help, including switching over to ABL001. Transformation is a real danger in this group of patients.
Practically speaking, I suppose I’d try intermittent dosing of dasatinib. NZ has access to imatinib, so that can be tried next. An allograft may be the only other option, though I note the non-compliance, age and co-morbidity in this patient.

David Ross: Agree with DY. Very difficult situation. Allografting probably the best option, but apparently not possible.
I’d probably try nilotinib if you can get it (acknowledging problems of vascular risk and compliance with bd dose and fasting requirement) on the basis that it has the least inhibition of c-kit and might be less myelosuppressive. My second choice would be dasatinib dose reduction, but that doesn’t deal with the poor BCR-ABL1 response. As a last resort you might even try interferon, if it’s still available in NZ, but with high risk Sokal I wouldn’t be optimistic.

Naranie Shanmuganathan: There is data for marrow aplasia in all TKIs especially imatinib and dasatinib which tend to improve with TKI interruption but the trade off is poor disease control. There are a couple of reports of nilotinib as well causing this degree of cytopenia although not as frequent as IM/DAS. My suggestion is nilotinib and then if that fails, compassionate access ABL001, esp if allografting is unable to be done

So two votes for nilotinib and one for intermittent dasatinib. Interferon and asciminib as next line therapy also suggested, Bad risk CML and poor drug adherence is a terrible combination. I doubt there is anything you can do at this stage which will enable this person to achieve a meaningful molecular response and she will likely progress to BC over the next few years. So QOL comes into play here. I would personally prefer low dose (or intermittent) dasatinib because she tolerates it well and it is easy to take, with an aim of maintaining haematological control for as long as possible. If you were confident that she could cope with the twice daily fasting requirements of nilotinib that would be reasonable too – it would also provide a pathway to asciminib access since you need to fail all available drugs first. I don’t think asciminib holds any great hopes here though, so this shouldn’t be the main motivation.
Tim Hughes
ORIGINAL CASE:
A 67-year old woman, CML-CP diagnosed September 2017. Presented with blood counts of WCC 300, 3.3% blasts, platelets 1000, baso 6%, big spleen. Marrow blasts <1%. Unsurprisingly was high risk on Sokal. Immediate cytoreduction with HU then imatinib. Her WBC was normal after 3 weeks but she defaulted from follow-up and relapsed having stopped her treatment in mid-2018. After a bit of a pep talk she restarted treatment and regained a haematological response but never any sort of molecular response.

I switched her to dasatinib in November 2018 based on the failure to achieve molecular response. Her mutation screen was negative then.

Her attendance at clinic hasn’t been exemplary and she did stop treatment once but I believe she has been compliant with dasatinib for the last six months based on the pick up of scripts at the right times from her pharmacy.

Another reason for believing she was taking dasatinib was that after several missed blood tests she pitched up in May 2019 with pancytopenia – Hb 63, platelets 36, neutrophils 1.1. Her marrow was virtually aplastic but she still managed to have 23% BCR-ABL on peripheral blood and 100% positive for 9;22 on karyotyping.

I stopped her dasatinib, her blood counts have recovered but her BCR-ABL is back to 43%. Would welcome your advice on where to go next. As well as age not on her side she is a smoker, has had “problematic” drinking in the past, AF and mild heart failure so I don’t think SCT was ever an option.

Hello. really tough case., We have similar case of lady age 64y who developed severe neutropenia and thrombocytopenia on imatinib 400mg. Bone marrow biopsy revealed cellularity od 10%. After several breaks lasting at least 3 months, after some recovery we have decided to switched her on nilotinib. For almost one year on nilotinib she was only od 400mg with again several mainly severe neutropenic episodes lasting more than a month each. Only in deep neutropenia she was treated with occasionally G-CSF in fear not to push CML towards blastic phase. Finally, after full 6 months of cumulative nilotinib treatment she achieved major CyR and nilotinib was escalated to 600mg daily. After a cumulative 12 months of nilotinib treatment she achieved complete CyR, currently persisting for 3 more years but without frank MR3 (swinging between MR2 and ME3). Bone marrow biopsy in time of achievement of CCyR was again hypocelullar for the age of patient. We decided not to increase nilotinib to 800mg due to persistence of marginal neutropenia and trhrombocytopenia (ANC 1.2 and Plc 80 G/L), as any TFR regiment would not be the option in such case.,
Therefore I vote for nilotinib again.

ORIGINAL CASE:
A 67-year old woman, CML-CP diagnosed September 2017. Presented with blood counts of WCC 300, 3.3% blasts, platelets 1000, baso 6%, big spleen. Marrow blasts <1%. Unsurprisingly was high risk on Sokal. Immediate cytoreduction with HU then imatinib. Her WBC was normal after 3 weeks but she defaulted from follow-up and relapsed having stopped her treatment in mid-2018. After a bit of a pep talk she restarted treatment and regained a haematological response but never any sort of molecular response.

I switched her to dasatinib in November 2018 based on the failure to achieve molecular response. Her mutation screen was negative then.

Her attendance at clinic hasn’t been exemplary and she did stop treatment once but I believe she has been compliant with dasatinib for the last six months based on the pick up of scripts at the right times from her pharmacy.

Another reason for believing she was taking dasatinib was that after several missed blood tests she pitched up in May 2019 with pancytopenia – Hb 63, platelets 36, neutrophils 1.1. Her marrow was virtually aplastic but she still managed to have 23% BCR-ABL on peripheral blood and 100% positive for 9;22 on karyotyping.

I stopped her dasatinib, her blood counts have recovered but her BCR-ABL is back to 43%. Would welcome your advice on where to go next. As well as age not on her side she is a smoker, has had “problematic” drinking in the past, AF and mild heart failure so I don’t think SCT was ever an option.